Polyoxypropylene/polyoxyethylene copolymers with improved biological activity

ABSTRACT

The present invention comprises novel preparations of polyoxypropylene/polyoxyethylene copolymers which retain the therapeutic activity of the commercial preparations, but are substantially free from the undesirable effects which are inherent in the prior art preparations. Because the preparations of polyoxypropylene/polyoxyethylene copolymers which comprise the present invention are a less polydisperse population of molecules than the prior art polyoxypropylene/polyoxyethylene copolymers, the biological activity of the copolymers is better defined and more predictable.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 08/657,161,filed Jun. 3, 1996 now U.S. Pat. No. 5,699,387, of application Ser. No.08/087,136, filed Jul. 2, 1993, now U.S. Pat. No. 5,523,490, which is acontinuation of Ser. No. 07/847,874 filed Mar. 13, 1992, now abandonedwhich is a continuation-in-part of U.S. patent application Ser. No.07/673,289, filed Mar. 19, 1991, now abandoned.

TECHNICAL FIELD

The present invention relates to a preparation ofpolyoxypropylene/polyoxyethylene copolymer which has an improvedtoxicity and efficacy profile. The present invention also includespolyoxypropylene/polyoxyethylene block copolymers with a polydispersityvalue of less than approximately 1.05.

BACKGROUND OF THE INVENTION

Certain polyoxypropylene/polyoxyethylene copolymers have been found tohave beneficial biological effects when administered to a human oranimal. These beneficial biological effects are summarized as follows:

Polyoxypropylene/polyoxyethylene Copolymers as Rheologic Agents

The copolymers can be used for treating circulatory diseases eitheralone or in combination with other compounds, including but not limitedto, fibrinolytic enzymes, anticoagulants, free radical scavengers,antiinflammatory agents, antibiotics, membrane stabilizers and/orperfusion media. These activities have been described in U.S. Pat. Nos.4,801,452, 4,873,083, 4,879,109, 4,837,014, 4,897,263, 5,064,643;5,028,599; 5,047,236; 5,089,260; 5,017,370; 5,078,995; 5,032,394;5,041,288; 5,071,649; 5,039,520; 5,030,448; 4,997,644; 4,937,070;5,080,894; and 4,937,070, all of which are incorporated herein byreference.

The polyoxypropylene/polyoxyethylene copolymers have been shown to havequite extraordinary therapeutic activities. The surface-activecopolymers are useful for treating pathologic hydrophobic interactionsin blood and other biological fluids of humans and animals. Thisincludes the use of a surface-active copolymer for treatment of diseasesand conditions in which resistance to blood flow is pathologicallyincreased by injury due to the presence of adhesive hydrophobic proteinsor damaged membranes. This adhesion is produced by pathologicalhydrophobic interactions and does not require the interaction ofspecific ligands with their receptors. Such proteins and/or damagedmembranes increase resistance in the microvasculature by increasingfriction and reducing the effective radius of the blood vessel. It isbelieved that the most important of these proteins is soluble fibrin.

Pathological hydrophobic interactions can be treated by administering tothe animal or human suffering from a condition caused by a pathologicalhydrophobic interaction an effective amount of a surface-activecopolymer. The surface-active copolymer may be administered as asolution by itself or it may by administered with another agent,including, but not limited to, a fibrinolytic enzyme, an anticoagulant,or an oxygen radical scavenger.

The method described in the foregoing patents comprises administering toan animal or human an effective amount of a surface-active copolymerwith the following general formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein a is an integer such that the hydrophobe represented by (C₃ H₆O) has a molecular weight of approximately 950 to 4000 daltons,preferably about 1200 to 3500 daltons, and b is an integer such that thehydrophile portion represented by (C₂ H₄ O) constitutes approximately50% to 95% by weight of the compound.

A preferred surface-active copolymer is a copolymer having the followingformula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein the molecular weight of the hydrophobe (C₃ H₆ O) isapproximately 1750 daltons and the total molecular weight of thecompound is approximately 8400 daltons.

The surface-active copolymer is effective in any condition where thereis a pathological hydrophobic interaction between cells and/ormolecules. These interactions are believed to be caused by 1) a higherthan normal concentration of fibrinogen, 2) generation of intravascularor local soluble fibrin, especially high molecular weight fibrin, 3)increased friction in the microvasculature, or 4) mechanical or chemicaltrauma to blood components. All of these conditions cause an increase inpathological hydrophobic interactions of blood components such as cellsand molecules.

It is believed that fibrin, especially soluble fibrin, increasesadhesion of cells to one another, markedly increases friction in smallblood vessels and increases viscosity of the blood, especially at lowshear rates. The effects of the surface-active copolymer are believed tobe essentially lubrication effects because they reduce the frictioncaused by the adhesion.

Although not wanting to be bound by the following hypothesis, it isbelieved that the surface-active copolymer acts according to thefollowing mechanism: Hydrophobic interactions are crucial determinantsof biologic structure. They hold the phospholipids together in membranesand protein molecules in their native configurations. An understandingof the biology of the surface-active copolymer is necessary toappreciate the biologic activities of the compound. Water is a stronglyhydrogen bonding liquid which, in its fluid state, forms bonds in alldirections with surrounding molecules. Exposure of a hydrophobicsurface, defined as any surface which forms insufficient bonds withwater, produces a surface tension or lack of balance in the hydrogenbonding of water molecules. This force can be exceedingly strong. Thesurface tension of pure water is approximately 82 dynes/cm. Thistranslates into a force of several hundred thousand pounds per squareinch on the surface molecules.

As two molecules or particles with hydrophobic surfaces approach, theyadhere avidly. This adhesion is driven by the reduction in free energywhich occurs when water molecules transfer from the stressednon-hydrogen bonding hydrophobic surface to the non-stressed bulk liquidphase. The energy holding such surfaces together, the work of adhesion,is a direct function of the surface tension of the particles:¹

    W.sub.AB =γA+γB-γAB

where W_(AB) =work of adhesion or the energy necessary to separate onesquare centimeter of particle interface AB into two separate particles,γA and γB are the surface tensions of particle A and particle B, γAB theinterfacial tension between them.

Consequently, any particles or molecules in the circulation whichdevelop significant surface tensions will adhere to one anotherspontaneously. Such adhesion within membranes and macromolecules isnecessary to maintain their integrity. We use the term "normalhydrophobic interaction" to describe such forces. Under normalcircumstances, all cells and molecules in the circulation havehydrophilic non-adhesive surfaces. Receptors and ligands which modulatecell and molecular interactions are generally located on the mosthydrophilic exposed surfaces of cells and molecules where they are freeto move about in the aqueous media and to interact with one another.Special carrier molecules are necessary to transport lipids and otherhydrophobic substances in the circulation. In body fluids such as blood,nonspecific adhesive forces between mobile elements are extremelyundesirable. These forces are defined as "pathologic hydrophobicinteractions"=0 because they restrict movement of normally mobileelements and promote inappropriate adhesion of cells and molecules.

In damaged tissue, hydrophobic domains normally located on the interiorof cells and molecules may become exposed and produce pathologicadhesive surfaces whose interaction compounds the damage. Fibrindeposited along vessel walls also provide an adhesive surface. Suchadhesive surfaces appear to be characteristic of damaged tissue. It isbelieved that the ability of the surface-active copolymer to bind toadhesive hydrophobic surfaces and convert them to non-adhesive hydratedsurfaces closely resembling those of normal tissues underlies itspotential therapeutic activities in diverse disease conditions.

Adhesion due to surface tension described above is different from theadhesion commonly studied in biology. The commonly studied adhesion isdue to specific receptor ligand interactions. In particular, it isdifferent from the receptor-mediated adhesion of the fibrinogen--vonWillibrands factor family of proteins.²

Both the hydrophilic and hydrophobic chains of the surface-activecopolymer have unique properties which contribute to biologic activity.The hydrophilic chains of polyoxyethylene (POE) are longer than those ofmost surfactants and they are flexible. They bind water avidly byhydrogen bond acceptor interactions with ether-linked oxygens. Theselong, strongly hydrated flexible chains are relatively incompressibleand form a barrier to hydrophobic surfaces approaching one another. Thehydroxyl moieties at the ends of the molecule are the only groupscapable of serving as hydrogen bond donors. There are no charged groups.

This extremely limited repertoire of binding capabilities probablyexplains the inability of the molecule to activate host mediator andinflammatory mechanisms. The POE chains are not necessarily inert,however. Polyoxyethylene can bind cations by ion-dipole interactionswith oxygen groups. The crown polyethers and reverse octablock copolymerionophores are examples of such cation binding.³ It is possible that theflexible POE chains form configurations which bind and modulate calciumand other cation movements in the vicinity of damaged membranes or otherhydrophobic structures.

The hydrophobic component of the surface-active copolymer is large, weakand flexible. The energy with which it binds to a cell membrane orprotein molecule is less than the energy which holds the membranephospholipids together or maintains the tertiary conformation of theprotein. Consequently, unlike common detergents which dissolve membranelipids and proteins, the surface-active copolymer adheres to damagedspots on membranes and prevents propagation of the injury.

The ability of the surface-active copolymer to block adhesion offibrinogen to hydrophobic surfaces and the subsequent adhesion ofplatelets and red blood cells is readily demonstrated in vitro. Mostsurfactants prevent adhesion of hydrophobic particles to one another,however, the surface-active copolymer has a unique balance of propertieswhich optimize the anti-adhesive activity while minimizing toxicity.Thus, the surface-active copolymer is not routinely used by biochemistswho use nonionic surfactants to lyse cells or dissolve membraneproteins. The surface-active copolymer protects cells from lysis. Thehydrophobe effectively competes with damaged cells and molecules toprevent pathologic hydrophobic interactions, but cannot disrupt the muchstronger normal hydrophobic interactions which maintain structuralintegrity.

The viscosity of blood is generally assumed to be the dominantdeterminant of flow through vessels with a constant pressure andgeometry. In the smallest vessels, such as those in damaged tissue,other factors become significant. When the diameter of the vessel isless than that of the cell, the blood cell must deform in order to enterthe vessel and then must slide along the vessel wall producing friction.The deformability of blood cells entering small vessels has beenextensively studied⁴ but the adhesive or frictional component has not.The adhesion of cells to vessel walls is generally attributed tospecific interactions with von Willebrand's factor and other specificadhesive molecules.⁵ Our data suggests that in pathologic situations,friction resulting from nonspecific physicochemical adhesion between thecell and the vessel wall becomes a major determinant of flow.

Mathematically, both the strength of adhesion between two particles andthe friction force which resists sliding of one along the other aredirect functions of their surface tensions which are largely determinedby their degree of hydrophobic interaction. The friction of a cellsliding through a small vessel consists of an adhesion component and adeformation component⁶ which are in practice difficult to separate:

    F=Fa+Fd

where F is the friction of cells, Fa is the adhesion component and Fd isthe deformation component.

The deformation component within a vessel differs from that required forentry into the vessel. It may be similar to that which occurs in largervessels with blood flowing at a high rate of shear.⁷ Friction withinblood vessels has been studied very little, but undoubtedly involves thesame principles which apply to polymer systems in which the frictionforce correlates directly with the work of adhesion:⁸

    Fa=k WA+c

where Fa is the adhesional component of the friction force, WA the workof adhesion, and k and c constants which pertain to the particularsystem studied. Many lubricants act as thin films which separate the twosurfaces and reduce adhesion.⁹

The effects of the surface-active copolymer on microvascular blood flowwere evaluated in several models ranging from artificial in vitrosystems where critical variables could be rigidly controlled to in vivosystems mimicking human disease. First, the surface-active copolymer canbe an effective lubricant when used at therapeutic concentrations in amodel designed to simulate movement of large cells through smallvessels. It markedly reduced the adhesive component of friction, but hadno detectable effect on the deformation component of friction. Second,the surface-active copolymer greatly accelerates the flow through thenarrow channels formed by the thrombogenic surfaces of glass and air. Adrop of blood was placed on a cover slip and viewed under a microscopewith cinemicroscopy during the time it took the blood to flow to theedges of the cover slip in response to gentle pressure. Thesurface-active copolymer inhibited the adhesion of platelets to theglass and maintained the flexibility of red cells which enabled them topass through the microscopic channels. While the surface-activecopolymer did not inhibit the formation of rouleaux by red cells, it didcause the rouleaux to be more flexible and more easily disrupted. Third,the surface-active copolymer increases the flow of blood throughtortuous capillary-sized fibrin-lined channels by over 20-fold. Itdecreased viscosity of the blood by an amount (10%) far too small toaccount for the increased flow.

In a more physiologic model, the surface-active copolymer increasedcoronary blood flow by a similar amount in isolated rat hearts perfusedwith human red blood cells at a 30% hematocrit following ischemicdamage.

In an in vivo model of stroke produced by ligature of the middlecerebral artery of rabbits, the surface-active copolymer increases bloodflow to ischemic brain tissue. As much as a two-fold increase wasmeasured by a hydrogen washout technique. In each of these models, therewere controls for hemodilution and there was no measurable effect onviscosity at any shear rate measured.

It is believed that available data suggests that the surface-activecopolymer acts as a lubricant to increase blood flow through damagedtissues. It blocks adhesion of hydrophobic surfaces to one another andthereby reduces friction and increases flow. This hypothesis isstrengthened by the observation that the surface-active copolymer haslittle effect on blood flow in normal tissues where such frictionalforces are small.¹⁰

The surface-active copolymers are not metabolized by the body and arequickly eliminated from the blood. The half-life of the copolymer in theblood is believed to be approximately two hours. It is to be understoodthat the surface-active copolymer in the improved fibrinolyticcomposition is not covalently bound to any of the other components inthe composition nor is it covalently bound to any proteins.

The surface-active copolymer can be administered with a fibrinolyticenzyme, a free radical scavenger, or it can be administered alone fortreatment of certain circulatory conditions which either are caused byor cause pathological hydrophobic interactions of blood components.These conditions include, but not limited to, myocardial infarction,stroke, bowel or other tissue infarctions, malignancies, adultrespiratory distress syndrome (ARDS), disseminated intravascularcoagulation (DIC), diabetes, unstable angina pectoris, hemolytic uremicsyndrome, red cell fragmentation syndrome, heat stroke, retained fetus,eclampsia, malignant hypertension, burns, crush injuries, fractures,trauma producing shock, major surgery, sepsis, bacterial, parasitic,viral and rickettsial infections which promote activation of thecoagulation system, central nervous system trauma, and during andimmediately after any major surgery. It is believed that treatment ofthe pathological hydrophobic interactions in the blood that occurs inthese conditions significantly reduces microvascular and othercomplications that are commonly observed.

The surface-active copolymer is also effective in increasing thecollateral circulation to undamaged tissues with compromised bloodsupply. Such tissues are frequently adjacent to areas of vascularocclusion. The mechanism appears to be reducing pathological hydrophobicinteractions in small blood vessels. Circulatory conditions where thesurface-active copolymers are effective include, but are not limited to,cerebral thrombosis, cerebral embolus, myocardial infarction, unstableangina pectoris, transient cerebral ischemic attacks, intermittentclaudication of the legs, plastic and reconstructive surgery, balloonangioplasty, peripheral vascular surgery, and orthopedic surgery,especially when using a tourniquet.

The surface-active copolymer has little effect on the viscosity ofnormal blood at shear rates ranging from 2.3 sec⁻¹ (low) to 90 sec⁻¹(high). However, it markedly reduces the abnormally high viscosity foundin postoperative patients and in those with certain pathologicconditions. This observation posed two questions: 1) what caused theelevated whole blood viscosity in these patients and, 2) by whatmechanisms did the surface-active copolymer, which has only minoreffects on the blood viscosity of healthy persons, normalize pathologicelevations in viscosity?

It is generally accepted that hematocrit and plasma fibrinogen levelsare the major determinants of whole blood viscosity. This has beenconfirmed in normal individuals and in many patients with inflammatoryconditions. However, these factors could not explain the changes thatwere observed. In patients having coronary artery cardiac bypasssurgery, it was found that hematocrit fell an average of 23±4% andfibrinogen fell 48±9% within six hours after surgery. The viscosity didnot decrease as expected, but increased from a mean of 23±2 to 38±4centipoise (at a shear rate of 2.3 sec⁻¹). Viscosities in excess of 100were found in some patients. The abnormally high viscosity of blood wasassociated with circulating high molecular weight polymers of solublefibrin.¹¹ The soluble fibrin levels rose from 19±5 μg/ml to 43±6 μg/mlduring surgery. These studies utilized a calorimetric enzymatic assayfor soluble fibrin¹² and Western blotting procedures with SDS agarosegels to determine the molecular weight of the large protein polymers.¹³

In the absence of specific receptors, cells and molecules in thecirculation adhere to one another if the adherence reduces the freeenergy or surface tension between them. An assessment of the surfacetension of various components of the blood can be made by measuringcontact angles.

Red blood cells, lymphocytes, platelets, neutrophils all have contactangles in the range of 14 to 17 degrees. Peripheral blood proteins, suchas albumin, α₂ macroglobulin, and Hageman factor have contact angles inthe slightly lower range of 12-15. This means that these proteins haveno adhesive energy for the cells. In contrast, fibrinogen has a contactangle of 24 degrees and soluble fibrin of 31. Consequently, fibrinogenadheres weakly to red blood cells and other cells in the circulationpromoting rouleaux formation. Fibrin promotes a very much strongeradhesion than fibrinogen because of its elevated contact angle and itstendency to form polymers with fibrinogen. Soluble fibrin in thecirculation produces the increased adhesion which results in a verymarkedly increased viscosity at low shear rates. This adhesion alsoinvolves the endothelial walls of the blood vessels. If the adhesiveforces are insufficient to slow movement of cells, they produce anincreased friction. This is especially important in the very small bloodvessels and capillaries whose diameters are equal to or less than thatof the circulating cells. The friction of cells sliding through thesesmall vessels is significant. The surface-active copolymer blocks theadhesion of fibrinogen and fibrin to hydrophobic surfaces of cells andendothelial cells. This prevents their adhesion and lubricates them sothere is a greatly reduced resistance to flow. This can be measured onlypartially by measurements of viscosity.

Whether a certain fibrinogen level is sufficient to cause a problem incirculation is dependent upon several parameters of the individualpatient. High hematocrits and high levels of fibrinogen are widelyregarded as the primary contributors to increased viscosity. However,elevated fibrinogen levels are frequently associated with elevatedsoluble fibrin in the circulation. Careful studies have demonstratedthat the fibrin is frequently responsible for the most severe changes.The normal level of fibrinogen is 200-400 μg/ml. It has been determinedthat, in most patients, fibrinogen levels of greater than approximately800 μg/ml will cause the high blood viscosity at the low shear ratesmentioned hereinabove. The normal level of soluble fibrin has beenreported to be approximately 9.2±1.9.¹⁴ Using the Wiman and Ranby assay,viscosity at low shear rates was unacceptably high above about 15 μg/ml.It must be understood that soluble fibrin means molecular species thathave a molecular weight of from about 600,000 to several million.

Numerous methods have been used for demonstrating soluble fibrin. Theseinclude cryoprecipitation especially cryofibrinogen. Heparin has beenused to augment the precipitate formation. Ethanol and protamine alsoprecipitate fibrin from plasma. Modem techniques have demonstrated thatthe soluble fibrin in the circulation is generally complexed withsolubilizing agents. These are most frequently fibrinogen or fibrindegradation products. Des AA fibrin in which only the fibrin of peptideA moieties have been cleaved, tends to form relatively small aggregatesconsisting of one molecule of fibrin with two of fibrinogen. If both theA and B peptides have been cleaved to produce des AABB fibrin, then muchlarger aggregates are produced in the circulation. Fibrin degradationproducts can polymerize with fibrin to produce varying size aggregatesdepending upon the particular product involved.

Soluble fibrin in the circulation can markedly increase blood viscosity,especially at low shear rates. However, the relevance of this forclinical situations remains unclear. Viscosity assesses primarily theaggregation of red blood cells which is only one of many factors whichdetermine in vivo circulation. Other factors affected by soluble fibrinare the endothelial cells, white blood cells and platelets. Solublefibrin is chemotactic for endothelial cells, adheres to them avidly andcauses their disorganization. It also has stimulatory effects for whiteblood cells, especially macrophages. Some of the effects of solublefibrin may be mediated by specific receptors on various types of cells.However, since the free energy, as measured by contact angles of solublefibrin, is less than that of any other plasma protein, it adheres avidlyby a nonspecific hydrophobic interactions to virtually all formedelements in the blood.

Circulating soluble fibrin is normally cleared by macrophages andfibrinolytic mechanisms without producing damage. However, if theproduction of soluble fibrin is too great or if the clearance mechanismshave been compromised or if complicating disease factors are present,then soluble fibrin can induce deleterious reactions.

Soluble fibrin is produced in damaged or inflamed tissues. Consequently,its effects are most pronounced in these tissues where it coatsendothelial cells and circulating blood cells in a fashion whichmarkedly reduces perfusion. The largest effects are in the small bloodvessels where soluble fibrin coating the endothelial cells and whiteblood cells produces a severe increase in friction to the movement ofwhite cells through the small vessels. Friction appears to be a muchmore severe problem with white blood cells and red blood cells becausethey are larger and much more rigid.

If production of soluble fibrin is sufficient, then effects are noticedin other areas. The best studied is the adult respiratory distresssyndrome where soluble fibrin produced in areas of damaged tissueproduces microthrombi and other processes in the lungs which can causepulmonary failure. However, lesser degrees of vascular compromise can bedemonstrated in many other organs.

Soluble fibrin, either alone or in complex with fibrinogen and othermaterials, is now recognized as being a major contributor to thepathogenesis of a diverse range of vascular diseases ranging fromcoronary thrombosis through trauma, burns, reperfusion injury followingtransplantation or any other condition where there has been localized orgeneralized activation of coagulation. A recent study demonstrated thatvirtually all patients with acute myocardial infarction or unstableangina pectoris have markedly elevated levels of soluble fibrin in theircirculation.

An example of the effects of soluble fibrin has been shown in studiesusing dogs. A normal dog is subjected to a hysterectomy. Then, while theanimal is still under anesthesia, the external jugular vein is carefullydissected. Alternatively, the vein may be occluded by gentle pressurewith the fingers for seven minutes. It is examined by scanning electronmicroscopy for adhesion of fibrin, red blood cells and other formedelements.

One finds that very few cells adhere to the endothelia of veins fromdogs which had not undergone hysterectomy, whether or not there had beenstasis produced by seven minutes occlusion. Similarly, there was only asmall increase in adhesion of red blood cells to the endothelium of thejugular vein in animals who had undergone hysterectomy. If, however, theanimals had a hysterectomy in addition to mild seven minute occlusion ofthe veins, then there was a striking increase in adhesion of formedelements of blood to the endothelial surfaces in some cases producingfrank mural thrombi. Both red blood cells and fibrin were visiblyadherent to the endothelial surfaces. In addition, there was disruptionof the normal endothelial architecture. All of the animals had elevatedlevels of soluble fibrin after the surgery. This model demonstrates theeffects of soluble fibrin produced by relatively localized surgery toproduce a greatly increased risk of deep vein thrombosis at a distantsite.

The surface-active copolymer addresses the problems of fibrin andfibrinogen in the blood by inhibiting the adhesion of fibrin,fibrinogen, platelets, red blood cells and other detectable elements ofthe blood stream. It blocks the formation of a thrombus on a surface.The surface-active copolymer has no effect on the viscosity of water orplasma. However, it markedly increases the rate of flow of water andplasma in small segments through tubes. The presence of air interfacesat the end of the columns or air bubbles which provide a significantsurface tension produce a friction along the walls of the tubes. Thesurface-active copolymer reduces this surface tension and the frictionand improves flow. This is an example whereby the surface-activecopolymer improves flow of fluid through tissues through a tube eventhough it has no effect on the viscosity of the fluid as usuallymeasured.

The surface-active copolymer has only a small effect on the viscosity ofwhole blood from normal individuals. It has little effect on theincrease that occurs with high hematocrit. However, it has an effect onthe very large increase in viscosity at low shear rates thought to becaused by soluble fibrin and fibrinogen polymers.

Recent studies demonstrate that the surface-active copolymer also hasthe ability to protect myocardial and other cells from a variety ofnoxious insults. During prolonged ischemia, myocardial cells undergo"irreversible injury." Cells which sustain irreversible injury aremorphologically intact but are unable to survive when returned to anormal environment. Within minutes of reperfusion with oxygenated blood,cells containing such occult lesions develop swelling and contractionbands and die.

Irreversibly injured myocardial cells have mechanical and osmoticfragility and latent activation of lipases, proteases and other enzymes.Reperfusion initiates a series of events including calcium loading, cellswelling, mechanical membrane rupture and the formation of oxygen freeradicals which rapidly destroy the cell. The surface-active copolymerretards such injury in the isolated perfused rat heart model. Themechanisms probably include osmotic stabilization and increasedmechanical resistance in a fashion similar to that known for red bloodcells.

The protective effects of the surface-active copolymer on the myocardiumare not limited to the myocardial cells. It also protects theendothelial cells of the microvasculature as assessed morphologically.By maintaining the integrity of such cells and helping to restore andmaintain non-adhesive surfaces, the surface-active copolymer tends toreduce the adhesion of macromolecules and cells in the microvasculature,to reduce coronary vascular resistance and to retard development of theno reflow phenomenon.

Examples of conditions where the surface-active copolymer can be used isin the treatment of sickle cell disease and preservation of organs fortransplantation. In both of these embodiments, blood flow is reducedbecause of pathologic hydrophobic interactions.

During a sickle cell crisis, sickled red blood cells aggregate becauseof the abnormal shape of the cells. In many cases, there are highconcentrations of soluble fibrin due to disseminated intravascularcoagulation. This results in pathological hydrophobic interactionsbetween blood cells, cells lining the blood vessels and soluble fibrinand fibrinogen. By administering to the patient the surface-activecopolymer, blood flow is increased and tissue damage is thereby reduced.The surface-active copolymer may be given prior to a sickle cell crisisto prevent onset of the crisis. In addition, the solution with theeffective amount of surface-active copolymer may also contain aneffective amount of anticoagulant.

In organs that have been removed from a donor for transplantation, thetissue is damaged due to ischemia and lack of blood. Preferably, thesurface-active copolymer is mixed with a perfusion medium. The perfusionmedia that can be used with the surface-active copolymer are well knownto those of ordinary skill in the art. The perfusion media can also bewhole blood or plasma. The solution can be perfused through the organthereby reducing the damage to the tissue. Because the tissue damage isreduced by perfusing the organ with the surface-active copolymersolution, the time the organ is viable and therefore the time the organcan be transplanted is increased.

Because the surface-active copolymer improves flow of blood throughdiseased or damaged tissue with minimal effect on blood flow in normaltissue, it is contemplated that the surface-active copolymer includes amethod for delivering drugs to damaged tissue comprising the step ofadministering to the animal or human a solution containing an effectiveamount of a drug, and an effective amount of the surface-activecopolymer.

Any drug that has an activity in diseased or damaged tissue is suitablefor use with the surface-active copolymer. These drugs include:

1. antimicrobial drugs

antibiotics

antifungal drugs

antiviral drugs

antiparasitic drugs;

2. antifungal drugs;

3. chemotherapeutic drugs for treating cancers and certain infections;

4. free radical scavenger drugs, including those drugs that prevent theproduction of free radicals;

5. fibrinolytic drugs;

6. perfusion media;

7. anti-inflammnatories, including, but not limited to, both steroidsand nonsteroid antiinflammatory drugs;

8. membrane stabilizers, such as dilantin;

9. anticoagulants;

10. ionotropic drugs, such as calcium channel blockers;

11. autonomic nervous system modulators.

Polyoxypropylene/polyoxyethylene Copolymers as Adjuvants

Other polyoxypropylene/polyoxyethylene copolymers are also useful as anadjuvant and a vaccine which is comprised of an antigen and an improvedadjuvant. In one embodiment, the antigen is admixed with an effectiveamount of a surface-active copolymer having the following generalformula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein the molecular weight of the hydrophobe (C₃ H₆ O) is betweenapproximately 4500 to 5500 daltons and the percentage of hydrophile (C₂H₄)) is between approximately 5% and 15% by weight.

The improved vaccine also comprises an antigen and an adjuvant whereinthe adjuvant comprises a surface-active copolymer with the followinggeneral formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O) .sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein the molecular weight of the hydrophobe (C₃ H₆ O) is betweenapproximately 3000 to 5500 daltons and the percentage of hydrophile(C2H₄ O) is between approximately 5% and 15% by weight which isformulated as a water-in-oil emulsion. The copolymers destabilizecommonly used water-in-oil vaccine emulsions, but surprisingly increasetheir efficacy and increase stability if the usual emulsifying agentsare omitted.

The improved vaccine also comprises an antigen and an adjuvant whereinthe adjuvant comprises a surface-active copolymer with the followinggeneral formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein the molecular weight of the hydrophobe (C₃ H₆ O) is betweenapproximately 3000 to 5500 daltons and the percentage of hydrophile (C₂H₄ O) is between approximately 5% and 15% by weight, and alipopolysaccharide (LPS) derivative. The adjuvant comprising acombination of LPS and surface-active copolymer produces a synergy ofeffects in terms of peak titer, time to reach peak titer and length oftime of response. In addition, the combination tends to increase theprotective IgG2 isotypes.

The adjuvants also comprise an octablock copolymer (poloxamine) with thefollowing general formula: ##STR1## wherein: the molecular weight of thehydrophobe portion of the octablock copolymer consisting of (C₃ H₆ O) isbetween approximately 5000 and 7000 daltons;

a is a number such that the hydrophile portion represented by (C₂ H₄ O)constitutes between approximately 10% and 40% of the total molecularweight of the compound;

b is a number such that the (C₃ H₆ O) portion of the octablock copolymerconstitute between approximately 60% and 90% of the compound and alipopolysaccharide derivative.

The (C₃ H₆ O) portion of the copolymer can constitute up to 95% of thecompound. The (C₂ H₄ O) portion of the copolymer can constitute as lowas 5% of the compound.

The combination of lipid conjugated polysaccharide with copolymer and animmunomodulating agent such as monophosphoryl lipid A, induces theproduction of a strong IgG response in which all of the subclasses ofIgG are present. In particular, the IgG2 and IgG3 subclasses which areprotective against pneumococcal infections are predominant. This is anunexpected finding because there is no protein or peptide in theimmnunogen preparation. It is believed that peptide moieties areessential for stimulating T cells which are required for production ofthese isotypes. Others have reported that polysaccharides are incapableof stimulating T cells. Nevertheless, the combination of copolymer,lipid conjugated polysaccharide and immunomodulating agent is able toproduce such a response. The adjuvant activity of the poloxamers and thepoloxamines is described in detail in copending U.S. patent applicationSer. No. 07/544,831, which is incorporated herein by reference.

Polyoxypropylene/polyoxyethylene Copolymers as Antiinfective Agents

Another group of polyoxypropylene/polyoxyethylene copolymers inhibit thegrowth of bacteria and viruses. For example, these surface-activecopolymers have been shown to inhibit HIV viruses, Mycobacteria speciesand Toxoplasma gondii.

The surface-active copolymers are effective in treating a viralinfection in a human or animal including infections caused by the HIVvirus or related strains. The present invention provides a compositionthat can be administered to patients who are infected with HIV virusesor similar viruses. The surface-active copolymer is effective ininhibiting or suppressing the replication of the HIV virus and relatedvirus strains in cells.

The surface-active copolymers are useful for treating infections causedby microorganisms when used alone or with a conventional antibiotic.Several conventional antibiotics that can be used with thesurface-active copolymer include, but are not limited to, rifampin,isoniazid, ethambutol, gentamicin, tetracycline, and erythromycin.

The surface-active copolymer has the following general formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein a is an integer such that the hydrophobe represented by (C₃ H₆O) has a molecular weight of about 1200 to 5300 daltons, preferablyabout 1750 to 4500 daltons, and b is an integer such that the hydrophileportion represented by (C₂ H₄ O) constitutes approximately 10% to 50% byweight of the compound.

The antiinfective activity of the poloxamers is described in detail incopending U.S. patent application Ser. No. 07/760,808, which isincorporated herein by reference.

Polyoxypropylene/polyoxyethylene Copolymers as Growth Stimulators andImmune Stimulators

Certain of the polyoxypropylene/polyoxyethylene copolymers are capableof effecting biological systems in several different ways. Thebiologically-active copolymers are capable of stimulating the growth ofan organism, stimulating the motor activity of an organism, stimulatingthe production of T-cells in the thymus, peripheral lymphoid tissue, andbone marrow cells of an animal, and stimulating immune responsiveness ofpoultry.

The biologically-active copolymers also have a wide variety of effectson individual cells. These compounds have ionophoric activity, i.e.,they cause certain ions to be transported across cell membranes. Thecompounds can cause non-cytolytic mast cell degranulation withsubsequent histamine release. In addition, it has been found thatcertain members of this class of biologically-active copolymers arecapable of specifically killing certain cancer cell lines.

Certain,,of the biologically-active copolymers can be administeredorally to animals to stimulate the growth of food animals such aschickens and swine. These and other biological activities are discussedin detail in copending U.S. patent application Ser. Nos. 07/107,358 and07/610,417, which are incorporated herein by reference.

Polyoxypropylene/polyoxyethylene Copolymer Structure

The surface-active copolymer blocks are formed by condensation ofethylene oxide and propylene oxide at elevated temperature and pressurein the presence of a basic catalyst. However, there is statisticalvariation in the number of monomer units which combine to form a polymerchain in each copolymer. The molecular weights giver are approximationsof the average weight of copolymer molecule in each preparation. A moredetailed discussion of the preparation of these compounds is found inU.S. Pat. No. 2,674,619, which is incorporated herein by reference. Amore general discussion of the structure of poloxamers and poloxamineblock copolymers can be found in Schmolka, I. R., "A Review of BlockPolymer Surfactants", J. AM. OIL CHEMISTS' SOC., 54:110-116 (1977),which is incorporated herein by reference.

It has been determined that the commercially available preparations ofpolyoxypropylene/polyoxyethylene copolymers vary widely relative to thesize and configuration of the constituent molecules. For example, thepreparation of poloxamer 188 that is purchased from BASF (Parsippany,N.J.) has a published structure of a molecular weight of the hydrophobe(C₃ H₆ O) of approximately 1750 daltons and the total molecular weightof the compound of approximately 8400 daltons. In reality, the compoundis composed of molecules which range from a molecular weight of lessthan 3,000 daltons to over 20,000 daltons. The molecular diversity anddistribution of molecules of commercial poloxamer 188 is illustrated bybroad primary and secondary peaks detected using gel permeationchromatography.

In addition to the wide variation in polymer size in the poloxamerpreparations currently available, it has been further determined thatthese fractions contain significant amounts of unsaturation. It isbelieved that this unsaturation in the polymer molecule is responsible,at least in part, for the toxicity and variable biological activities ofthe available poloxamer preparations.

Thus, the wide diversity of molecules which are present in thecommercially available polyoxypropylene/polyoxyethylene copolymers makeprediction of the biological activity difficult. In addition, as isshown in the poloxamer 188 preparations, the presence of other molecularspecies in the preparation can lead to unwanted biological activities.

The surface-active copolymer poloxamer 188 has been used as anemulsifier for an artificial blood preparation containingperfluorocarbons. It has been reported that patients receiving theartificial blood preparations have exhibited toxic reactions. The toxicreactions included activation of complement¹⁵, paralysis of phagocytemigration¹⁶, and cytotoxicity to human and animal cells in tissueculture¹⁷. Efforts using supercritical fluid fractionation to reduce thetoxicity of the copolymers proved only partially successful.¹⁸ Inaddition, in toxicological studies in beagle dogs, infusion of poloxamer188 was shown to result in elevated liver enzymes, (SGOT) and increasedorgan weights (kidney). Histologic evaluation of the kidney demonstrateda dose related cytoplasmic vacuolation of the proximal tubularepithelial cells.

The enormous variation that can occur in biological activity when onlysmall changes are made in chain length in the poloxamer copolymers isillustrated in Hunter, et al.¹⁹ The authors show that a difference of10% in the chain length of the polyoxyethylene portions of the poloxamerpolymer can mean the difference between an excellent adjuvant and noadjuvant activity at all. Poloxamer 121 has a molecular weight ofapproximately 4400 daltons and contains approximately 10% by weight ofpolyoxyethelene. Poloxamer 122 has a molecular weight of approximately5000 daltons and contains approximately 20% by weight ofpolyoxyethelene. The amount of polyoxypropylene in each molecule isapproximately the same. As shown in Hunter, et al., when poloxamer 121was used as an adjuvant with bovine serum albumin, the antibody titerswere 67,814±5916. When poloxamer 122 was used as an adjuvant with bovineserum albumin under the same conditions, the antibody titer against BSAwas 184±45. The control titer without any adjuvant was <100. Thus, arelatively small change in the chain length of the poloxamer can resultin enormous changes in biological activity.

Because the commercially available sources of thepolyoxypropylene/polyoxyethylene copolymers have been reported toexhibit toxicity as well as variation in biological activity, what isneeded is a preparation of polyoxypropylene/polyoxyethylene copolymerswhich retain the therapeutic activities of the commercial preparationsbut are free from their other biological activities such as toxicity. Inaddition, what is needed is a preparation ofpolyoxypropylene/polyoxyethylene copolymers which is less polydispersein molecular weight and contains less unsaturation and therefore is moreefficacious.

SUMMARY OF THE INVENTION

The present invention comprises novel preparations ofpolyoxypropylene/polyoxyethylene copolymers which retain the therapeuticactivity of the commercial preparations, but are free from theundesirable effects which are inherent in the prior art preparations.Because the polyoxypropylene/polyoxyethylene copolymers which comprisethe present invention are a less polydisperse population of moleculesthan the prior art polyoxypropylene/polyoxyethylene copolymers, thebiological activity of the copolymers is better defined and morepredictable. In addition, the polyoxypropylene/polyoxyethylenecopolymers which comprise the present invention are substantially freeof unsaturation.

The present invention also comprises a polyoxypropylene/polyoxyethylenecopolymer which has the following formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein the molecular weight of the hydrophobe (C₃ H₆ O) isapproximately 1750 daltons and the total molecular weight of thecompound is approximately 8400 daltons. The compound has apolydispersity value of less than approximately 1.05.

It has been determined that the toxicity exhibited by the commerciallyavailable surface-active copolymer poloxamer 188 is primarily due to thesmall amounts of high and low molecular weight molecules that arepresent as a result of the manufacturing process. The high molecularweight molecules (those greater than 15,000 daltons) are probablyresponsible for activation of the complement system. The low molecularweight molecules (those lower than 5,000 daltons) have detergent-likephysical properties which can be toxic to cells in culture. In addition,the low molecular weight molecules have unsaturated polymers present inthe population.

The optimal rheologic molecules of poloxamer 188 are approximately 8,400to 9400 daltons. It has also been determined that poloxamer 188molecules above 15,000 and below 5,000 daltons are less effectiverheologic agents and exhibit unwanted side effects. A preparationcontaining molecules between 5,000 and t5,000 daltons is a moreefficient rheologic agent.

The present invention also includes a method of preparingpolyoxypropylene/polyoxyethylene block copolymers with polydispersityvalues of less than 1.05. The method of preparing a non-toxicsurface-active copolymer includes first condensing propylene oxide witha base compound containing a plurality of reactive hydrogen atoms toproduce polyoxypropylene polymer and then condensing ethylene oxide withthe polyoxypropylene polymer to produce apolyoxypropylene/polyoxyethylene block copolymer with the followinggeneral formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein the polydispersity value of the copolymer is less than 1.05, theimprovement being the purification of the polyoxypropylene polymer toremove any truncated polymers before condensation with the ethyleneoxide. The purification of the polyoxypropylene polymer can be by gelpermeation chromatography.

Accordingly, it is an object of the present invention to provide asurface-active copolymer with a higher proportion of therapeuticallyactive molecules while also eliminating molecules responsible for toxiceffects.

It is another object of the present invention to provide a morehomogeneous polyoxypropylene/polyoxyethylene copolymer relative to themolecular weight range.

It is another object of the present invention to provide a preparationof polyoxyethylene/polyoxypropylene block copolymer with apolydispersity value of less than 1.05.

It is another object of the present invention to provide a preparationof polyoxyethylene/polyoxypropylene block copolymer with substantiallyno unsaturation.

It is another object of the present invention to provide asurface-active copolymer with the therapeutic activity of poloxamer 188that will not activate complement.

It is yet another object of the present invention to provide a purifiedpoloxamer 188 that can be used safely in both humans and animals intreating tissue that has been damaged by ischemia.

It is yet another object of the present invention to provide asurface-active copolymer that can be used safely in both humans andanimals in treating tissue that has been damaged by reperfusion injury.

It is yet another object of the present invention to provide asurface-active copolymer that can be used safely in both humans andanimals as a vaccine adjuvant.

It is another object of the present invention to provide asurface-active copolymer with the therapeutic activity of poloxamer 188that is not cytotoxic.

It is yet another object of the present invention to provide asurface-active copolymer that can be used safely in both humans andanimals in treating stroke.

It is yet another object of the present invention to provide asurface-active copolymer which has less renal toxicity and lessdetergent-like activity.

It is yet another object of the present invention to provide asurface-active copolymer that can be used safely in both humans andanimals as an antimicrobial agent.

It is yet another object of the present invention to provide asurface-active copolymer that can be used safely in both humans andanimals as an antibacterial, an antiviral, an antifungal and anantiprotozoa agent.

It is yet another object of the present invention to provide asurface-active copolymer that can be used safely in both humans andanimals in treating myocardial damage.

It is yet another object of the present invention to provide asurface-active copolymer that can be used safely in both humans andanimals in treating adult respiratory distress syndrome.

These and other objects, features and advantages of the presentinvention will become apparent after a review of the following detaileddescription of the disclosed embodiments and the appended claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a poloxamer grid for naming poloxmer compounds.

FIG. 2 is a chromatogram of commercially available poloxamer 188subjected to gel permeation chromatography.

FIG. 3 is a chromatogram of fraction 1 of the poloxamer 188 collectedfrom the chromatographic run described in Example I.

FIG. 4 is a chromatogram of fraction 2 of the poloxamer 188 collectedfrom the chromatographic run described in Example I.

FIG. 5 is a chromatogram of fraction 3 of the poloxamer 188 collectedfrom the chromatographic run described in Example I.

FIG. 6 is a chromatogram of fraction 4 of the poloxamer 188 collectedfrom the chromatographic run described in Example I.

FIG. 7 is a chromatogram of fraction 5 of the poloxamer 188 collectedfrom the chromatographic run described in Example I.

FIG. 8 is a chromatogram of fraction 6 of the poloxamer 188 collectedfrom the chromatographic run described in Example I.

FIGS. 9A through 9C are gel permeation chromatograms of unfractionatedand fractionated poloxamer 760.5.

FIGS. 10A through 10C are nuclear magnetic spectra of the fractionsrepresented in FIGS. 9A through 9C.

FIGS. 11A through 11C are gel permeation chromatograms of threefractions of poloxamer 188.

FIGS. 12A through 12C are gel permeation chromatograms of unfractionatedand fractionated poloxamer 331.

DETAILED DESCRIPTION

Although the prior art preparations of polyoxypropylene/polyoxyethyleneblock copolymers may have been suitable for industrial uses, it has beendetermined that the newly discovered uses for the copolymers astherapeutic agents require less polydisperse populations of molecules inthe preparations.

The present invention comprises polyoxypropylene/polyoxyethylenecopolymers that have a polydisperse value of less than 1.05. The novelcopolymers can be prepared by removing disparate molecules from theprior art preparation or by preparing the copolymer according to themethod that is contemplated as part of the present invention. The methodof preparation of the copolymers of the present invention is thepurification of the polyoxypropylene block of thepolyoxypropylene/polyoxyethylene copolymer before the polyoxyethyleneblocks are added to the molecule. In this way, the partially polymerizedpolyoxypropylene polymers are removed before the addition ofpolyoxyethylene polymers to the molecule. This results in a blockcopolymer that is within the physical parameters which are contemplatedas the present invention.

The present invention also comprises a polyoxypropylene/polyoxyethyleneblock copolymer which has the following formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein the molecular weight represented by the polyoxypropylene portionof the copolymer is between approximately 900 and 15000 daltons with amore preferred molecular weight of between 1,200 and 6500 daltons andthe molecular weight represented by the polyoxyethylene portion of thecopolymer constitutes between approximately 5% and 95% of the copolymerwith a more preferred range of between approximately 10% and 90% of thecopolymer and the polydispersity value is less than approximately 1.07.

The present invention also comprises a polyoxypropylene/polyoxyethyleneblock copolymer which has the following formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein the molecular weight of the hydrophobe (C₃ H₆ O) isapproximately 1750 daltons and the average molecular weight of thecompound is approximately 8300 to 9400 daltons. The compound has amolecular weight distribution ranging from approximately 5,000 to 15,000daltons with a preferred molecular weight range of between approximately7,000 to 12,000 daltons. In addition, the copolymer has substantially nounsaturation as measured by nuclear magnetic resonance.

The nomenclature of the poloxamer compounds is based on a poloxamer grid(FIG. 1). The poloxamer grid is the relationship between nomenclatureand composition of the various polymer members. The hydrophobe(polyoxypropylene) molecular weights are given as approximate midpointsof ranges. The first two digits of a poloxamer number on the grid,multiplied by 100, gives the approximate molecular weight of thehydrophobe. The last digit, times 10, gives the approximate weightpercent of the hydrophile (polyoxyethylene) content of thesurfactant..sup.° For example, poloxamer 407, shown in the upper righthand quadrant of the grid (FIG. 1), is derived from a 4000 molecularweight hydrophobe with the hydrophile comprising 70% of the totalmolecular weight of the copolymer. Another example is poloxmer 760.5which has a hydrophobe with a molecular weight of 7600 daltons and has ahydrophile which comprises 5% of the total molecular weight of thecopolymer.

The representative poloxamers that are described in this patentapplication along with their Pluronic® numbers are shown in Table I.

                  TABLE I                                                         ______________________________________                                        Poloxamer No.   Pluronic® No.                                                                        % POE                                              ______________________________________                                        188             F68        80%                                                331              L101       10%                                               760.5            L180.5      5%                                               1000.5           L331        5%                                               ______________________________________                                    

Although molecular weight averages are important and useful whencharacterizing polymers in general, it is important to know themolecular weight distribution of a polymer. Some processing and end-usecharacteristics (melt flow, flex life, tensile strength, etc.) are oftenpredicted or understood by observing the values and/or changes occurringin specific molecular weight averages. These values can also be assignedto biological properties of the polyoxypropylene/polyoxyethylenecopolymers. A list of the processing characteristics follows.

    ______________________________________                                        Molecular Weight                                                                             Processing                                                     Averages       Characteristics                                                ______________________________________                                        Mz             Flex life/stiffness                                            Mn             Brittleness, flow                                              Mw             Tensile strength                                               ______________________________________                                    

For example, the breadth of the distribution is known as thepolydispersity (D) and is usually defined as Mw/Mn. A monodispersesample is defined as one in which all molecules are identical. In such acase, the polydispersity (Mw/Mn) is 1.0. Narrow molecular weightstandards have a value of D near 1 and a typical polymer has a range of2 to 5. Some polymers have a polydispersity in excess of 20.

The equations for expressing polydispersity are as follows: ##EQU1##where: Area_(i) =area of the ith slice

M_(i) =molecular weight of the ith slice

Thus, by calculating the parameters listed above, one can specify acertain polydispersity that is acceptable for a pharmaceuticalpreparation. A high polydispersity value indicates a wide variation insize for the population of molecules in a given preparation while alower polydispersity value indicates less variation. Because molecularsize is an important determinant of biological activity, it is importantto restrict the dispersity of the molecules in the preparation in orderto achieve a more homogeneous biological effect. Thus, thepolydispersity measurement can be used to measure the dispersity ofmolecules in a preparation and correlates to that compound's potentialfor variation in biological activity.

It is to be understood that the polydispersity values that are describedherein were determined from chromatograms which were obtained using aModel 600E Powerline chromatographic system equipped with a columnheater module, a Model 410 refractive index detector, Maxima 820software package (all from Waters, Div. of Millipore, Milford, Mass.),two LiChrogel PS-40 columns and a LiChrogel PS-20 column in series (EMScience, Gibbstown, N.J.), and polyethylene glycol molecular weightstandards (Polymer Laboratories, Inc., Amherst, Mass.). Polydispersityvalues obtained using this system are relative to the chromatographicconditions, the molecular weight standards and the size exclusioncharacteristics of the gel permeation columns. Polydispersitymeasurements using different separation principles may give absolutepolydispersity values which are different from those described herein.However, one of ordinary skill in the art can easily convert anypolydispersity value that is obtained using a different separationmethod to the values described herein simply by running a single sampleon both systems and then comparing the polydispersity values from eachchromatogram.

In accordance with the present invention, a composition is provided thatis a polyoxypropylene/polyoxyethylene block copolymer that has apolydispersity value of less than 1.07. Preferably, the polydispersityvalue is less than approximately 1.05, with a most preferablepolydispersity value of 1.03. It is to be understood that the presentinvention includes, but is not limited to, poloxamer compounds andpoloxamine compounds.

Also in accordance with the present invention, a composition is providedthat is a surface-active copolymer comprising apolyoxypropylene/polyoxyethylene block copolymer with the followinggeneral formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein the total molecular weight of the copolymer is betweenapproximately 5,000 and 15,000 daltons, preferably a molecular weight ofbetween approximately 7,000 and 12,000 daltons and the molecular weightrepresented by the polyoxyethylene portion of the copolymer constitutesapproximately 80% of the copolymer.

One embodiment of the present invention comprises apolyoxypropylene/polyoxyethylene copolymer which has the followingformula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein the molecular weight of the hydrophobe (C₃ H₆ O) isapproximately 1750 daltons and the average molecular weight of thecompound is approximately 8300 to 9400 daltons. The polydispersity valueis less than approximately 1.05. A block copolymer corresponding to atleast these physical parameters has the beneficial biological effects ofthe prior art poloxamer 188 but does not exhibit the unwanted sideeffects which have been reported for the prior art compound. By reducingthe polydispersity value of the surface-active copolymer, it has beenfound that the toxicity associated with the prior art poloxamer 188 issignificantly reduced. However, the beneficial therapeutic activity ofthe modified poloxamer 188 is retained.

The surface-active copolymers of the present invention can be preparedin a number of ways. The polydispersity value can be reduced bysubjecting the prior art compounds to gel permeation chromatography. Inaddition, the compounds can be subjected to molecular sieving techniquesthat are known to those of ordinary skill in the art.

The surface-active copolymer of the present invention can be prepared inseveral ways. In the first method, commercially available poloxamer 188is subjected to gel permeation chromatography. The chromatogram that isobtained from this procedure is shown in FIG. 1.

As can be seen in FIG. 1, commercial poloxamer 188 is composed of abroad distribution of molecules with a peak molecular weight ofapproximately 7900 to 9500 daltons. This corresponds generally to thepublished molecular weight for poloxamer 188 of 8400 daltons. Thepublished molecular weight for poloxamer 188 is determined by thehydroxyl method. The end groups of polyether chains are hydroxyl groups.The number averaged molecular weight can be calculated from theanalytically determined "OH Number" expressed in mg KOH/g sample. Itshould be understood that the molecular weight of a polydispersecompound can be different depending upon the methodology used todetermine the molecular weight.

FIG. 1 also shows small secondary peaks or shoulders lying to the leftand right of the primary peak. These areas of the poloxamer 188chromatogram represent the high and low molecular weight moleculesrespectively. The high molecular weight species range in size fromapproximately 24,000 to 15,000 daltons. It is believed that these largermolecules have a greater capacity to activate complement compared to thelower molecular weight species. The shoulder on the right or lowermolecular weight side of the chromatogram is composed of moleculesbetween approximately 2,300 daltons and 5,000 daltons. This speciesrepresents compounds which have more detergent-like properties and arecytotoxic to cells.

Using the gel permeation chromatography procedure, it has beendetermined that a fraction of poloxamer 188 with molecules ranging fromapproximately 5,000 daltons to 15,000 daltons, preferably betweenapproximately 6,000 daltons and 13,000 daltons, with a peak atapproximately 8,700 daltons, represents a population of surface-activecopolymers which are essentially devoid of toxic activities while stillretaining the beneficial therapeutic activity of the commerciallyavailable poloxamer 188. This new composition is a much more homogeneouspreparation than those currently available and unexpectedly has fewerside effects than the prior art preparation.

It should be understood that the molecular weight range that isdescribed as the optimum range for the copolymer is to be considered theoutside range and that any population of molecules that fall within thatrange are considered as embodiments of the present invention.

The present invention also includes a novel method of preparing asurface-active copolymer composition with the specifications describedherein. The novel method involves the preparation of a uniformhydrophobic polyoxypropylene polymer and then proceed with the additionof the hydrophilic polyoxyethylene as is normally done. It is believedthat the toxic copolymers that are the result of the standard commercialmethod of preparing poloxamer 188 are due to truncated polymer chainsand to unsaturation in the polymer.

In practicing the present invention, the hydrophobic polyoxypropylenepolymer is purified to obtain a substantially uniform population ofpolyoxypropylene polymers. The purification can be performed using gelpermeation chromatography. However, any method known to one of ordinaryskill in the art which gives the desired range of polyoxypropylenepolymers can be used.

In preparing the improved rheologic reagent, the polyoxypropylenepolymer should have an average molecular weight of approximately 1750daltons with an approximate molecular weight range between 1,000 and2,600 daltons. The preferred molecular weight range is between 1,200 and2,400 daltons.

After the desired polyoxypropylene copolymer has been obtained, theethylene portion of the copolymer is added to both ends of the moleculeby standard methods well known to those of ordinary skill in the art.The final polymer population should have a polyoxyethylene compositionof approximately 20% of the total molecular weight of the molecule.

This invention is further illustrated by the following examples, whichare not to be construed in any way as imposing limitations upon thescope thereof. On the contrary, it is to be clearly understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which, after reading the description herein, maysuggest themselves to those skilled in the art without departing fromthe spirit of the present invention and/or the scope of the appendedclaims.

EXAMPLE I

Poloxamer 188 (BASF Corporation, Parsippany N.J.) is dissolved intetrahydrofuran at a concentration of 20 mg/mL. A Model 600E Powerlinechromatographic system equipped with a column heater module, a Model 410refractive index detector and Maxima 820 software package (all fromWaters, Div. of Millipore, Milford, Mass.) is used to fractionate thecommercially prepared poloxamer 188 copolymer. The chromatographicsystem is equipped with two LiChrogel PS-40 columns and a LiChrogelPS-20 column in series (EM Science, Gibbstown, N.J.). The LiChrogelPS-40 columns are 10 μm particle size and the LiChrogel PS-20 column is5 μm particle size. All columns are 7 mm by 25 cm in size.

200μL (4mg) of the poloxamer 188 in tetrahydrofuran is added to thecolumn and the sample is run with the columns and the detector at 40° C.The resulting chromatogram is shown in FIG. 2.

EXAMPLE II

The sample that was collected in Example I was fractionated into fivefractions and each fraction was run on the column as described inExample I. The chromatograms from the various chromatographic runs areshown in FIGS. 3 through 8. The fraction that demonstrates the leasttoxicity while retaining the therapeutic activity of the poloxamer 188is shown in FIG. 5. As can be clearly seen, the shoulders on either sideof the peak in FIG. 5 are absent.

The average molecular weight for each fraction is shown in Table II. Thechromatogram for each fraction is indicated in FIGS. 3 through 8.

                  TABLE II                                                        ______________________________________                                                       Time off    Molecular                                                                             Polydispersity                             Fraction                                                                              FIG.    Column (Min)                                                                              Wt.     Value                                     ______________________________________                                        1      3       11.5-12.0   17000   1.0400                                     2      4       12.0-12.5   10270   1.0474                                     3      5       12.5-13.0   8964     1.0280                                    4      6       13.0-13.5   8188     1.0332                                    5      7       13.5-14.0   5418     1.1103                                    6      8       14.0-14.5   3589     1.0459                                    ______________________________________                                    

The polydispersity value for the unfractionated poloxamer 188 is 1.0896.The fraction that most closely corresponds to poloxamer 188 is fraction3 which has a polydispersity value of approximately 1.0280.

EXAMPLE III

In a one-liter 3 neck round bottom flask equipped with a mechanicalstirrer, reflux condenser, thermometer and propylene oxide feed inlet,there is placed 57 grams (0.75 mol) of propylene glycol and 7.5 grams ofanhydrous sodium hydroxide. The flask is purged with nitrogen to removeair and heated to 120° C. with stirring until the sodium hydroxide isdissolved. Sufficient propylene oxide is introduced into the mixture asfast as it reacts until the product possesses a calculated molecularweight of approximately 1750 daltons. The product is cooled undernitrogen and the NaOH catalyst is neutralized with sulfuric acid and theproduct is then filtered. The final product is a water-insolublepolyoxypropylene glycol.

EXAMPLE IV

The polyoxypropylene glycol from Example III is dissolved intetrahydrofuran at a concentration of 20 mg/mL. A Model 600E Powerlinechromatographic system equipped with a column heater module, a Model 410refractive index detector and Maxima 820 software package (all fromWaters, Div. of Millipore, Milford, Mass.) is used to fractionate thecommercially prepared poloxamer 188 copolymer. The chromatographicsystem is equipped with two LiChrogel PS-40 columns and a LiChrogelPS-20 column in series (EM Science, Gibbstown, N.J.). The LiChrogelPS-40 columns are 10 μm particle size and the LiChrogel PS-20 column is5 μm particle size. All columns are 7 mm by 25 cm in size.

200μL (4mg) of the polyoxypropylene glycol in tetrahydrofuran is addedto the column and the sample is run with the columns and the detector at40° C. The fraction which corresponded to an average molecular weight of1750 daltons with a molecular weight distribution between 1,000 and2,600 daltons was collected. Other fractions were discarded.

EXAMPLE V

The purified polyoxypropylene glycol from Example IV was placed in thesame apparatus as described in Example III with an appropriate amount ofanhydrous sodium hydroxide. An appropriate amount of ethylene oxide wasadded at an average temperature of 120° C. using the same techniquedescribed in Example III. The amount of added ethylene oxidecorresponded to 20% of the total weight of the polyoxypropylene glycolbase plus the weight of added ethylene oxide.

This procedure results in a polyoxypropylene/polyoxyethylene blockcopolymer composed of molecules which are far more homogeneous relativeto molecular size and configuration compared to commercial preparations.

EXAMPLE VI

Fractions of poloxamer 760.5 prepared by gel permeation chromatographyand were analyzed for weight percent of oxyethylene and for unsaturationby NMR analysis as follows: Poloxamer 760.5 (BASF Corporation,Parsippany N.J.) is dissolved in tetrahydrofuran at a concentration of20 mg/mL. A Model 600E Powerline chromatographic system equipped with acolumn heater module, a Model 410 refractive index detector and Maxima820 software package (all from Waters, Div. of Millipore, Milford,Mass.) is used to fractionate the conmmercially prepared poloxamer 760.5copolymer. The chromatographic system is equipped with Ultrastyragel 103A and 500 A in series (Waters, Div. of Millipore, Milford, Mass.).Column size is 7.8 mm internal diameter by 30 cm. Precolumn filters#A-315 with removable 2μm fits (Upchurch Scientific, Oak Harbor, Wash.)were used for protection of the columns. 200μL (4mg) of the poloxamer760.5 in tetrahydrofuran is added to the column and the sample is runwith the columns at 40° C. and the detector at 45° C.

Sample one is an unfractionated sample of the polaxamer 760.5 asobtained from BASF Corporation (Parsipanny, N.J.) and is shown in FIG.9A. Fraction one is an early fraction from the chromatographic systemand is shown in FIG. 9B. Fraction two is a late fraction and is shown inFIG. 9C. All proton NMR analyses were performed in accordance with theNF procedure "Weight Percent Oxyethylene" on a Bruker 300 MHzinstrument.

The proton nuclear magnetic resonance spectra from FIGS. 9B and 9Cshowed slight ban broadening in the spectra when compared to theunfractionated sample. The late eluting fraction (Fraction 2) containsthe largest amount of unsaturation as noted by a doublet signal at about4.0 ppm. The proton spectra for the early eluting peak (Fraction 1)showed no impurities except water.

The weight percent oxyethylene was calculated for the samples. As can beseen from Table III, the early eluting fraction, which is the purestfraction, has the lowest percentage of oxyethylene. This fraction alsoshowed no unsaturation as measured by nuclear magnetic resonance. Usingthe poloxamer nomenclature system described above, the various fractionshave the following characteristics and poloxamer number.

                  TABLE III                                                       ______________________________________                                        Fraction  % POE.sup.a                                                                            MW.sup.b Poloxamer                                                                             Unsaturation.sup.c                        ______________________________________                                        Unfractionated                                                                          5.5      8135     760.5   Yes                                       Early Fraction                                                                          3.9      10856    104.4   No                                        Late Fraction                                                                           7.5      3085     291     Yes                                       ______________________________________                                         a. As measured by NMR                                                         b. Polyoxypropylene as measured by gel permeation chromatography              c. As measured by NMR                                                    

EXAMPLE VII

Poloxamer 188 (Pluronic® F68) was fractionated on a gel permeationchromatography system according to Example I. Three fractions werecollected. FIG. 11A shows Fraction 1, an early, high molecular weightfraction. FIG. 11B shows Fraction II, which is the major peak. FIG. 11Cshows Fraction III, a late eluting, lower molecular weight population ofmolecules. The percent oxyethylene of each fraction was determined byproton NMR using a 200 MHz NMR spectrophotometer. Approximately 10 mg ofeach sample was tested. Samples were prepared by adding approximately0.7 mL of CDCl₃ to each vial. The solution was filtered and transferredto a 5-mm NMR tube. One drop of D₂ O was added, and the tube was shakenprior to measurement.

                  TABLE IV                                                        ______________________________________                                        Fraction    % POE.sup.a                                                                              MW.sup.b Poloxamer                                     ______________________________________                                        Early       85         16,500   258                                           Middle Fraction                                                                           82         8652     178                                           Late Fraction                                                                             90         3751     039                                           ______________________________________                                         a. As measured by NMR                                                         b. As measured by gel permeation chromatography                          

As shown in Table IV, the early eluting, the large molecular weightfraction had a high percentage of oxyethylene and corresponded to apoloxamer 258. The middle fraction had the smallest percentage ofoxyethylene while the late eluting, small molecular weight fraction hadthe highest percentage of oxyethylene. The middle fraction had acalculated poloxamer number of 178 which corresponds closely to thedesired number of 188. The late fraction had a calculated poloxamernumber of 039. Thus, the commercially available poloxamer preparationhas a significant population of polymers which may be harmful in abiological system.

EXAMPLE VIII

Poloxamer 331 (Pluronic® L101) was fractionated according to theprotocol in Example VI. The chromatographs for unfractionated poloxamer331, an early eluting fraction and a late eluting fraction are shown inFIGS. 12A through 12C respectively. The NMR spectra for each sample wasthen determined as in Example VI. The results of these spectra andchromatograms are summarized in Table V.

                  TABLE V                                                         ______________________________________                                        Fraction  % POE.sup.a                                                                            MW.sup.b                                                                              Poloxamer                                                                             Unsaturation.sup.c                         ______________________________________                                        Unfractioned                                                                            17       4045    342     Yes                                        Early Fraction                                                                          15       4452    381     No                                         Late Fraction                                                                           31       1466    103     Yes                                        ______________________________________                                         a. As measured by NMR                                                         b. As measured by gel permeation chromatography                               c. As measured by NMR                                                    

When the poloxamer number for each fraction is calculated based on theempirical data collected, it is seen that the late fraction polymer is avery different poloxamer than the unfractionated preparation. Inaddition, the unsaturated population of polymers has been removed by thefractionation procedure.

It should be understood that the foregoing relates only to a preferredembodiment of the present invention and that numerous modifications oralterations may be made therein without departing from the spirit andthe scope of the invention as set forth in the appended claims.

¹ Adamson, AW, PHYSICAL CHEMISTRY OF SURFACES. 4th Ed., John Wiley &Sons, New York (1982).

² See generally, HEMOSTASIS AND THROMBOSIS, BASIC PRINCIPLES ANDCLINICAL PRACTICE, ed. by Colman, et al., J. B. Lipincott Company (1987)

³ Atkinson, T P, et al., "", AM. J. PHYSIOL. 254:C20 (1988).

⁴ Brooks, D E, and Evans, E A, Rheology of blood cells in CLINICALHEMORHEOLOGY, Applications in Cardiovascular and Hematological Disease,Diabetes, Surgery and Gynecology. S. Chien, J. Dormandy, E. Ernst, andA. Matrai, eds, Martinus Nijhoff Publishers, Dordrecht (1987).

⁵ Thompson, A R, and Harker, L A, MANUAL OF HEMOSTASIS AND THROMBOSIS,Edition 3, F. A. Davis Company, Philadelphia (1983).

⁶ Lee, L H, "Effect of surface energetics on polymer friction and wear",in ADVANCES IN POLYMER FRICTION AND WEAR, Polymer Science andTechnology, Vol. 5A. L. H Lee, editor, Plenum Press, New York (1974).

⁷ Brooks and Evans (1987), supra

⁸ Lee, (1974), supra

⁹ Adamson, (1982), supra

¹⁰ Grover, F. L., et al., "A nonionic surfactant and blood viscosity",ARCH SURG, 106:307 (1973).

¹¹ Papadea, C. and Hunter, R., "Effect of RheothRx® copolymer on bloodviscosity related to fibrin(ogen) concentration", FASEB J 2:A384 (1988).

¹² Wiman, B. and Rinby, M., "Determination of soluble fibrin in plasmaby a rapid and quantitative spectrophotometric assay", TOMB. HAEMOST,55:189 (1986).

¹³ Connaghan, D G, Francis, C W, Lane, D A, and Marder, V J, "Specificidentification of fibrin polymers, fibrinogen degradation products, andcross-linked fibrin degradation products in plasma and serum with a newsensitive technique", BLOOD, 65:589 (1985).

¹⁴ Wiman, B. and Ranby, M., "Determination of soluble fibrin in plasmaby a rapid and quantitative spectrophotometric assay", THROMB. HAEMOST.55:189 (1986).

¹⁵ Vercellotte, G. M, et al., "Activation of Plasma Complement byPerfluorocarbon Artificial Blood: Probable Mechanism of AdversePulmonary Reactions in Treated Patients and Rationale for CorticosteroidProphylaxis", BLOOD, Vol. 59, pp. 1299-1304 (1982).

¹⁶ Lane, T. A., et al., "Paralysis of phagocyte migration due to anartificial blood substitute", BLOOD, Vol. 64, pp. 400-405 (1984).

¹⁷ Lane, T. A., et al., "Reduction in the toxicity of a component of anartificial blood substitute by supercritical fluid fractionation",TRANSFUSION, Vol. 28, pp. 375-378 (1987).

¹⁸ Lane, T. A., et al., "Reduction in the toxicity of a component of anartificial blood substitute by supercritical fluid fractionation",TRANSFUSION, Vol. 28, pp. 375-378 (1987).

¹⁹ Hunter, et al., "The Adjuvant Activity of Nonionic Block PolymerSurfactants, mI. Characterization of Selected Biologically ActiveSurfaces", SCAND. J. IMMUNOL., Vol. 23, PP. 28-300 (1986).

²⁰ Henry, R. L., et al., "Burn Wound Coverings and the Use of PoloxamerPreparations", CRITICAL REVIEWS IN BIOCOMPATIBILITY, Vol. 5, No. 3, pp.207-220 (1989).

We claim:
 1. A substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition, wherein said substantially purepolyoxypropylene/polyoxyethylene block copolymer composition has lessunsaturation than a corresponding non-purepolyoxypropylene/polyoxyethylene block copolymer composition, saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition containing block copolymers with each of the blockcopolymers having the following general formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein a is an integer such that the molecular weight represented bythe polyoxypropylene portion of the respective block copolymer isbetween 900 Daltons and 15,000 Daltons and b is an integer such that themolecular weight represented by the polyoxyethylene portion of therespective block copolymer constitutes between 5% and 95% of therespective block copolymer and the polydispersity value is less thanapproximately 1.07.
 2. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim 1,wherein the polyoxypropylene portion of the respective block copolymerhas a molecular weight range of between 1,200 Daltons and 6,500 Daltons.3. A substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 1, wherein the polyoxyethylene portion of therespective block copolymer constitutes between 10% and 95% of therespective block copolymer.
 4. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim 1,wherein the polyoxyethylene portion of the respective block copolymerconstitutes between 5% and 15% of the respective block copolymer.
 5. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 1, wherein the polyoxyethylene portion of therespective block copolymer constitutes 20% of the respective blockcopolymer.
 6. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 1, wherein a and b are selectedsuch that the average total molecular weight of said substantially pureblock copolymer composition is between 5,000 Daltons and 15,000 Daltons.7. A substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 2, wherein a and b are selected such that theaverage total molecular weight of said substantially pure blockcopolymer composition is between 5,000 Daltons and 15,000 Daltons.
 8. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 3, wherein a and b are selected such that theaverage total molecular weight of said substantially pure blockcopolymer composition is between 5,000 Daltons and 15,000 Daltons.
 9. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 5, wherein a and b are selected such that theaverage total molecular weight of said substantially pure blockcopolymer composition is between 5,000 Daltons and 15,000 Daltons.
 10. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 4, wherein the average total molecular weight ofsaid substantially pure block copolymer composition is between 3,000Daltons and 5,500 Daltons.
 11. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim 4,wherein the average total molecular weight of said substantially pureblock copolymer composition is between 4,500 Daltons and 5,500 Daltons.12. A substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition of claim 1, wherein a is an integer such that themolecular weight of the polyoxypropylene portion of the respective blockcopolymer is 1,750 Daltons and the average total molecular weight ofsaid substantially pure block copolymer composition is between 8,300Daltons and 9,400 Daltons.
 13. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim 1,wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 1,750Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 8,400 Daltons.
 14. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 2, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 1,750Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 8,400 Daltons.
 15. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 3, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 1,750Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 8,400 Daltons.
 16. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 5, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 1,750Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 8,400 Daltons.
 17. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 1, wherein the average total molecular weight of saidsubstantially pure block copolymer composition is between 5,000 Daltonsand 15,000 Daltons and b is an integer such that the molecular weightrepresented by the polyoxyethylene portion of the respective blockcopolymer constitutes between 75% and 85% of the respective blockcopolymer.
 18. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 17, wherein b is an integer suchthat the molecular weight represented by the polyoxyethylene portion ofthe respective block copolymer constitutes 80% of the respective blockcopolymer.
 19. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 6, wherein the average totalmolecular weight of said substantially pure block copolymer compositionis between 7,000 and 12,000 Daltons.
 20. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim 7,wherein the average total molecular weight of said substantially pureblock copolymer composition is between 7,000 and 12,000 Daltons.
 21. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 8, wherein the average total molecular weight ofsaid substantially pure block copolymer composition is between 7,000 and12,000 Daltons.
 22. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim 9,wherein the average total molecular weight of said substantially pureblock copolymer composition is between 7,000 and 12,000 Daltons.
 23. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 18, wherein the average total molecular weight ofsaid substantially pure block copolymer composition is between 7,000 and12,000 Daltons.
 24. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim 1,wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 9,700Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 10,000 Daltons.
 25. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 1, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 3,400Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 4,000 Daltons.
 26. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 1, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is between950 Daltons and 4,000 Daltons and b is an integer such that themolecular weight represented by polyoxeythylene portion of therespective block copolymer constitutes between 50% and 95% of therespective block copolymer.
 27. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim 1,wherein the average total molecular weight of said substantially pureblock copolymer composition is between 5,000 Daltons and 15,000 Daltonsand a is an integer such that the molecular weight represented by thepolyoxypropylene portion of the respective block copolymer constitutesbetween 15% and 25% of the respective block copolymer.
 28. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 1, wherein the average total molecular weight ofsaid substantially pure block copolymer composition is between 1,200Daltons and 5,300 Daltons and a is an integer such that the molecularweight represented by the polyoxypropylene portion of the respectiveblock copolymer constitutes between 10% and 50% of the respective blockcopolymer.
 29. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 28, wherein the average totalmolecular weight of said substantially pure block copolymer compositionis between 1,750 Daltons and 4,500 Daltons.
 30. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim 1,wherein the average total molecular weight of said substantially pureblock copolymer composition is between 1,000 Daltons and 2,600 Daltonsand a is an integer such that the molecular weight represented by thepolyoxypropylene portion of the respective block copolymer constitutes20% of the respective block copolymer.
 31. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim30, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 1,200 Daltons and 2,400Daltons.
 32. A substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition, wherein said substantially purepolyoxypropylene/polyoxyethylene block copolymer composition is preparedby:(a) providing a non-purified polyoxypropylene/polyoxyethylene blockcopolymer composition prepared by first polymerizing propylene oxide andthereafter copolymerizing ethylene oxide therewith which results in theformation of at least(1) block copolymers with each of the blockcopolymers having the following general formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein a is an integer such that the molecular weight represented bythe polyoxypropylene portion of the respective block copolymer isbetween 900 daltons and 15,000 daltons and b is an integer such that themolecular weight represented by the polyoxyethylene portion constitutesbetween 5% and 95% of the respective block copolymer, and (2) at leastone impurity resulting from the manufacture of the non-purified blockcopolymer composition, wherein at least one impurity containsunsaturation; and (b) substantially removing the at least one impurityfrom the non-purified block copolymer composition resulting in saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition which thereby has the property of having less unsaturationthan the non-purified copolymer composition from which saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition is derived.
 33. A method of making a substantially purepolyoxypropylene/polyoxyethylene block copolymer composition, whereinsaid substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition is prepared by:(a) providing a non-purifiedpolyoxypropylene/polyoxyethylene block copolymer composition prepared byfirst polymerizing propylene oxide and thereafter copolymerizingethylene oxide therewith which results in the formation of at least(1)block copolymers with each of the block copolymers having the followinggeneral formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein a is an integer such that the molecular weight represented bythe polyoxypropylene portion of the respective block copolymer isbetween 900 daltons and 15,000 daltons and b is an integer such that themolecular weight represented by the polyoxyethylene portion constitutesbetween 5% and 95% of the respective block copolymer, and (2) at leastone impurity resulting from the manufacture of the non-purified blockcopolymer composition, wherein at least one impurity containsunsaturation; and (b) substantially removing the at least one impurityfrom the non-purified block copolymer composition resulting in saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition which thereby has the property of having less unsaturationthan the non-purified copolymer composition from which saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition is derived.
 34. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition, whereinsaid substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition is less renal toxic than a corresponding non-purepolyoxypropylene/polyoxyethylene block copolymer composition, saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition containing block copolymers with each of the blockcopolymers having the following general formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein a is an integer such that the molecular weight represented bythe polyoxypropylene portion of the respective block copolymer isbetween 900 daltons and 15,000 daltons and b is an integer such that themolecular weight represented by the polyoxyethylene portion of therespective block copolymer constitutes between 5% and 95% of therespective block copolymer.
 35. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition, whereinsaid substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition has less truncated polymer chains than a correspondingnon-pure polyoxypropylene/polyoxyethylene block copolymer composition,said substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition containing block copolymers with each of the blockcopolymers having the following general formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein a is an integer such that the molecular weight represented bythe polyoxypropylene portion of the respective block copolymer isbetween 900 daltons and 15,000 daltons and b is an integer such that themolecular weight represented by the polyoxyethylene portion of therespective block copolymer constitutes between 5% and 95% of therespective block copolymer.
 36. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition, whereinsaid substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition is less cytotoxic than a corresponding non-purepolyoxypropylene/polyoxyethylene block copolymer composition, saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition containing block copolymers with each of the blockcopolymers having the following general formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein a is an integer such that the molecular weight represented bythe polyoxypropylene portion of the respective block copolymer isbetween 900 daltons and 15,000 daltons and b is an integer such that themolecular weight represented by the polyoxyethylene portion of therespective block copolymer constitutes between 5% and 95% of therespective block copolymer.
 37. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition, whereinsaid substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition has less detergent-like activity than a correspondingnon-pure polyoxypropylene/polyoxyethylene block copolymer composition,said substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition containing block copolymers with each of the blockcopolymers having the following general formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein a is an integer such that the molecular weight represented bythe polyoxypropylene portion of the respective block copolymer isbetween 900 daltons and 15,000 daltons and b is an integer such that themolecular weight represented by the polyoxyethylene portion of therespective block copolymer constitutes between 5% and 95% of therespective block copolymer.
 38. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition, whereinsaid substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition is less renal toxic than a corresponding non-purepolyoxypropylene/polyoxyethylene block copolymer composition, saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition containing block copolymers with each of the blockcopolymers having the following general formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein the average total molecular weight of said substantially pureblock copolymer composition is between 5,000 and 15,000 Daltons and b isan integer such that the molecular weight represented by thepolyoxyethylene portion of the respective block copolymer constitutesbetween 5% and 95% of the respective block copolymer.
 39. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition, wherein said substantially purepolyoxypropylene/polyoxyethylene block copolymer composition has lesstruncated polymer chains than a corresponding non-purepolyoxypropylene/polyoxyethylene block copolymer composition, saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition containing block copolymers with each of the blockcopolymers having the following general formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein the average total molecular weight of said substantially pureblock copolymer composition is between 5,000 and 15,000 Daltons and b isan integer such that the molecular weight represented by thepolyoxyethylene portion of the respective block copolymer constitutesbetween 5% and 95% of the respective block copolymer.
 40. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition, wherein said substantially purepolyoxypropylene/polyoxyethylene block copolymer composition is lesscytotoxic than a corresponding non-pure polyoxypropylene/polyoxyethyleneblock copolymer composition, said substantially purepolyoxypropylene/polyoxyethylene block copolymer composition containingblock copolymers with each of the block copolymers having the followinggeneral formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein the average total molecular weight of said substantially pureblock copolymer composition is between 5,000 and 15,000 Daltons and b isan integer such that the molecular weight represented by thepolyoxyethylene portion of the respective block copolymer constitutesbetween 5% and 95% of the respective block copolymer.
 41. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition, wherein said substantially purepolyoxypropylene/polyoxyethylene block copolymer composition has lessdetergent-like activity than a corresponding non-purepolyoxypropylene/polyoxyethylene block copolymer composition, saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition containing block copolymers with each of the blockcopolymers having the following general formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein the average total molecular weight of said substantially pureblock copolymer composition is between 5,000 and 15,000 Daltons and b isan integer such that the molecular weight represented by thepolyoxyethylene portion of the respective block copolymer constitutesbetween 5% and 95% of the respective block copolymer.
 42. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition, wherein said substantially purepolyoxypropylene/polyoxyethylene block copolymer composition has lessunsaturation than a corresponding non-purepolyoxypropylene/polyoxyethylene block copolymer composition, saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition containing block copolymers with each of the blockcopolymers having the following general formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein the average total molecular weight of said substantially pureblock copolymer composition is between 5,000 and 15,000 Daltons and b isan integer such that the molecular weight represented by thepolyoxyethylene portion of the respective block copolymer constitutesbetween 5% and 95% of the respective block copolymer.
 43. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition, wherein said substantially purepolyoxypropylene/polyoxyethylene block copolymer composition is lessrenal toxic than a corresponding non-purepolyoxypropylene/polyoxyethylene block copolymer composition, saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition containing block copolymers with each of the blockcopolymers having the following general formula:

    HO(C.sub.2 H4O).sub.b (C.sub.3 H.sub.6 O).sub.a (C2H4O).sub.b H

wherein b is an integer such that the molecular weight represented bythe polyoxyethylene portion of the respective block copolymerconstitutes between 5% and 95% of the respective block copolymer, andwherein the substantially pure block copolymer composition comprisesgreater than 92.2 percent by weight of a middle molecular weightfraction when fractionated by gel chromatography.
 44. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition,wherein said substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition has less truncated polymer chains than acorresponding non-pure polyoxypropylene/polyoxyethylene block copolymercomposition, said substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition containing block copolymers with each of theblock copolymers having the following general formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein b is an integer such that the molecular weight represented bythe polyoxyethylene portion of the respective block copolymerconstitutes between 5% and 95% of the respective block copolymer, andwherein the substantially pure block copolymer composition comprisesgreater than 92.2 percent by weight of a middle molecular weightfraction when fractionated by gel chromatography.
 45. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition,wherein said substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition is less cytotoxic than a corresponding non-purepolyoxypropylene/polyoxyethylene block copolymer composition, saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition containing block copolymers with each of the blockcopolymers having the following general formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein b is an integer such that the molecular weight represented bythe polyoxyethylene portion of the respective block copolymerconstitutes between 5% and 95% of the respective block copolymer, andwherein the substantially pure block copolymer composition comprisesgreater than 92.2 percent by weight of a middle molecular weightfraction when fractionated by gel chromatography.
 46. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition,wherein said substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition has less detergent-like activity than acorresponding non-pure polyoxypropylene/polyoxyethylene block copolymercomposition, said substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition containing block copolymers with each of theblock copolymers having the following general formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein b is an integer such that the molecular weight represented bythe polyoxyethylene portion of the respective block copolymerconstitutes between 5% and 95% of the respective block copolymer, andwherein the substantially pure block copolymer composition comprisesgreater than 92.2 percent by weight of a middle molecular weightfraction when fractionated by gel chromatography.
 47. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition,wherein said substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition has less unsaturation than a correspondingnon-pure polyoxypropylene/polyoxyethylene block copolymer composition,said substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition containing block copolymers with each of the blockcopolymers having the following general formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein b is an integer such that the molecular weight represented bythe polyoxyethylene portion of the respective block copolymerconstitutes between 5% and 95% of the respective block copolymer, andwherein the substantially pure block copolymer composition comprisesgreater than 92.2 percent by weight of a middle molecular weightfraction when fractionated by gel chromatography.
 48. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition,wherein said substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition is prepared by:(a) providing a non-purifiedpolyoxypropylene/polyoxyethylene block copolymer composition prepared byfirst polymerizing propylene oxide and thereafter copolymerizingethylene oxide therewith which results in the formation of at least(1)block copolymers with each of the block copolymers having the followinggeneral formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 0).sub.b H

wherein a is an integer such that the molecular weight represented bythe polyoxypropylene portion of the respective block copolymer isbetween 900 daltons and 15,000 daltons and b is an integer such that themolecular weight represented by the polyoxyethylene portion constitutesbetween 5% and 95% of the respective block copolymer, and (2) at leastone impurity resulting from the manufacture of the non-purified blockcopolymer composition, wherein the impurity has the property of beingrenal toxic to a human body; and (b) substantially removing the at leastone impurity from the non-purified block copolymer composition resultingin said substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition which thereby has the property of being less renaltoxic than the non-purified copolymer composition from which saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition is derived.
 49. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition, whereinsaid substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition is prepared by:(a) providing a non-purifiedpolyoxypropylene/polyoxyethylene block copolymer composition prepared byfirst polymerizing propylene oxide and thereafter copolymerizingethylene oxide therewith which results in the formation of at least(1)block copolymers with each of the block copolymers having the followinggeneral formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein a is an integer such that the molecular weight represented bythe polyoxypropylene portion of the respective block copolymer isbetween 900 daltons and 15,000 daltons and b is an integer such that themolecular weight represented by the polyoxyethylene portion constitutesbetween 5% and 95% of the respective block copolymer, and (2) at leastone impurity resulting from the manufacture of the non-purified blockcopolymer composition, wherein the impurity contains truncated polymerchains; and (b) substantially removing the at least one impurity fromthe non-purified block copolymer composition resulting in saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition which thereby has the property of having less truncatedpolymer chains than the non-purified block copolymer composition fromwhich said substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition is derived.
 50. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition, whereinsaid substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition is prepared by:(a) providing a non-purifiedpolyoxypropylene/polyoxyethylene block copolymer composition prepared byfirst polymerizing propylene oxide and thereafter copolymerizingethylene oxide therewith which results in the formation of at least(1)block copolymers with each of the block copolymers having the followinggeneral formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein a is an integer such that the molecular weight represented bythe polyoxypropylene portion of the respective block copolymer isbetween 900 daltons and 15,000 daltons and b is an integer such that themolecular weight represented by the polyoxyethylene portion constitutesbetween 5% and 95% of the respective block copolymer, and (2) at leastone impurity resulting from the manufacture of the non-purified blockcopolymer composition, wherein the impurity has the property of beingcytotoxic to a human body; and (b) substantially removing the impurityfrom the non-purified block copolymer composition resulting in saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition which thereby has the property of being less cytotoxic thanthe non-purified block copolymer composition from which saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition is derived.
 51. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition, whereinsaid substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition is prepared by:(a) providing a non-purifiedpolyoxypropylene/polyoxyethylene block copolymer composition prepared byfirst polymerizing propylene oxide and thereafter copolymerizingethylene oxide therewith which results in the formation of at least(1)block copolymers with each of the block copolymers having the followinggeneral formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 0).sub.b H

wherein a is an integer such that the molecular weight represented bythe polyoxypropylene portion of the respective block copolymer isbetween 900 daltons and 15,000 daltons and b is an integer such that themolecular weight represented by the polyoxyethylene portion constitutesbetween 5% and 95% of the respective block copolymer, and (2) at leastone impurity resulting from the manufacture of the non-purified blockcopolymer composition, wherein the impurity imparts detergent-likeactivity to the non-purified block copolymer composition; and (b)substantially removing the impurity from the non-purified blockcopolymer composition resulting in said substantially purepolyoxypropylene/polyoxyethylene block copolymer composition whichthereby has less detergent-like activity than the non-purified blockcopolymer composition from which said substantially purepolyoxypropylene/polyoxyethylene block copolymer composition is derived.52. A method of making a substantially purepolyoxypropylene/polyoxyethylene block copolymer composition, whereinsaid substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition is prepared by:(a) providing a non-purifiedpolyoxypropylene/polyoxyethylene block copolymer composition prepared byfirst polymerizing propylene oxide and thereafter copolymerizingethylene oxide therewith which results in the formation of at least(1)block copolymers with each of the block copolymers having the followinggeneral formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein a is an integer such that the molecular weight represented bythe polyoxypropylene portion of the respective block copolymer isbetween 900 daltons and 15,000 daltons and b is an integer such that themolecular weight represented by the polyoxyethylene portion constitutesbetween 5% and 95% of the respective block copolymer, and (2) at leastone impurity resulting from the manufacture of the non-purified blockcopolymer composition, wherein the impurity has the property of beingrenal toxic to a human body; and (b) substantially removing the impurityfrom the non-purified block copolymer composition resulting in saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition which thereby has the property of being less renal toxicthan the non-purified copolymer composition from which saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition is derived.
 53. A method of making a substantially purepolyoxypropylene/polyoxyethylene block copolymer composition, whereinsaid substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition is prepared by:(a) providing a non-purifiedpolyoxypropylene/polyoxyethylene block copolymer composition prepared byfirst polymerizing propylene oxide and thereafter copolymerizingethylene oxide therewith which results in the formation of at least(1)block copolymers with each of the block copolymers having the followinggeneral formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein a is an integer such that the molecular weight represented bythe polyoxypropylene portion of the respective block copolymer isbetween 900 daltons and 15,000 daltons and b is an integer such that themolecular weight represented by the polyoxyethylene portion constitutesbetween 5% and 95% of the respective block copolymer, and (2) at leastone impurity resulting from the manufacture of the non-purified blockcopolymer composition, wherein the impurity contains truncated polymerchains; and (b) substantially removing the impurity from thenon-purified block copolymer composition resulting in said substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition whichthereby has the property of having less truncated polymer chains thanthe non-purified block copolymer composition from which saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition is derived.
 54. A method of making a substantially purepolyoxypropylene/polyoxyethylene block copolymer composition, whereinsaid substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition is prepared by:(a) providing a non-purifiedpolyoxypropylene/polyoxyethylene block copolymer composition prepared byfirst polymerizing propylene oxide and thereafter copolymerizingethylene oxide therewith which results in the formation of at least(1)block copolymers with each of the block copolymers having the followinggeneral formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein a is an integer such that the molecular weight represented bythe polyoxypropylene portion of the respective block copolymer isbetween 900 daltons and 15,000 daltons and b is an integer such that themolecular weight represented by the polyoxyethylene portion constitutesbetween 5% and 95% of the respective block copolymer, and (2) at leastone impurity resulting from the manufacture of the non-purified blockcopolymer composition, wherein the impurity has the property of beingcytotoxic to a human body; and (b) substantially removing the impurityfrom the non-purified block copolymer composition resulting in saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition which thereby has the property of being less cytotoxic thanthe non-purified block copolymer composition from which saidsubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition is derived.
 55. A method of making a substantially purepolyoxypropylene/polyoxyethylene block copolymer composition, whereinsaid substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition is prepared by:(a) providing a non-purifiedpolyoxypropylene/polyoxyethylene block copolymer composition prepared byfirst polymerizing propylene oxide and thereafter copolymerizingethylene oxide therewith which results in the formation of at least(1)block copolymers with each of the block copolymers having the followinggeneral formula:

    HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H

wherein a is an integer such that the molecular weight represented bythe polyoxypropylene portion of the respective block copolymer isbetween 900 daltons and 15,000 daltons and b is an integer such that themolecular weight represented by the polyoxyethylene portion constitutesbetween 5% and 95% of the respective block copolymer, and (2) at leastone impurity resulting from the manufacture of the non-purified blockcopolymer composition, wherein the impurity imparting detergent-likeactivity to the non-purified block copolymer composition; and (b)substantially removing the impurity from the non-purified blockcopolymer composition resulting in said substantially purepolyoxypropylene/polyoxyethylene block copolymer composition whichthereby has less detergent-like activity than the non-purified blockcopolymer composition from which said substantially purepolyoxypropylene/polyoxyethylene block copolymer composition is derived.56. A substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition of claim 34, wherein the polyoxypropylene portionof the respective block copolymer has a molecular weight range ofbetween 1,200 Daltons and 6,500 Daltons.
 57. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim34, wherein the polyoxyethylene portion of the respective blockcopolymer constitutes between 10% and 95% of the respective blockcopolymer.
 58. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 34, wherein the polyoxyethyleneportion of the respective block copolymer constitutes between 5% and 15%of the respective block copolymer.
 59. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim34, wherein the polyoxyethylene portion of the respective blockcopolymer constitutes 20% of the respective block copolymer.
 60. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 34, wherein a and b are selected such that theaverage total molecular weight of said substantially pure blockcopolymer composition is between 5,000 Daltons and 15,000 Daltons.
 61. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 56, wherein a and b are selected such that theaverage total molecular weight of said substantially pure blockcopolymer composition is between 5,000 Daltons and 15,000 Daltons.
 62. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 57, wherein a and b are selected such that theaverage total molecular weight of said substantially pure blockcopolymer composition is between 5,000 Daltons and 15,000 Daltons.
 63. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 59, wherein a and b are selected such that theaverage total molecular weight of said substantially pure blockcopolymer composition is between 5,000 Daltons and 15,000 Daltons.
 64. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 58, wherein the average total molecular weight ofsaid substantially pure block copolymer composition is between 3,000Daltons and 5,500 Daltons.
 65. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim58, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 4,500 Daltons and 5,500Daltons.
 66. A substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition of claim 34, wherein a is an integer such that themolecular weight of the polyoxypropylene portion of the respective blockcopolymer is 1,750 Daltons and the average total molecular weight ofsaid substantially pure block copolymer composition is between 8,300Daltons and 9,400 Daltons.
 67. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim34, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 1,750Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 8,400 Daltons.
 68. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 56, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 1,750Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 8,400 Daltons.
 69. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 57, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 1,750Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 8,400 Daltons.
 70. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 59, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 1,750Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 8,400 Daltons.
 71. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 34, wherein the average total molecular weight of saidsubstantially pure block copolymer composition is between 5,000 Daltonsand 15,000 Daltons and b is an integer such that the molecular weightrepresented by the polyoxyethylene portion of the respective blockcopolymer constitutes between 75% and 85% of the respective blockcopolymer.
 72. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 71, wherein b is an integer suchthat the molecular weight represented by the polyoxyethylene portion ofthe respective block copolymer constitutes 80% of the respective blockcopolymer.
 73. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 34, wherein the average totalmolecular weight of said substantially pure block copolymer compositionis between 7,000 and 12,000 Daltons.
 74. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim56, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 7,000 and 12,000 Daltons.75. A substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition of claim 57, wherein the average total molecularweight of said substantially pure block copolymer composition is between7,000 and 12,000 Daltons.
 76. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim59, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 7,000 and 12,000 Daltons.77. A substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition of claim 72, wherein the average total molecularweight of said substantially pure block copolymer composition is between7,000 and 12,000 Daltons.
 78. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim34, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 9,700Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 10,000 Daltons.
 79. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 34, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 3,400Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 4,000 Daltons.
 80. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 34, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is between950 Daltons and 4,000 Daltons and b is an integer such that themolecular weight represented by polyoxeythylene portion of therespective block copolymer constitutes between 50% and 95% of therespective block copolymer.
 81. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim34, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 5,000 Daltons and 15,000Daltons and a is an integer such that the molecular weight representedby the polyoxypropylene portion of the respective block copolymerconstitutes between 15% and 25% of the respective block copolymer.
 82. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 34, wherein the average total molecular weight ofsaid substantially pure block copolymer composition is between 1,200Daltons and 5,300 Daltons and a is an integer such that the molecularweight represented by the polyoxypropylene portion of the respectiveblock copolymer constitutes between 10% and 50% of the respective blockcopolymer.
 83. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 82, wherein the average totalmolecular weight of said substantially pure block copolymer compositionis between 1,750 Daltons and 4,500 Daltons.
 84. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim34, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 1,000 Daltons and 2,600Daltons and a is an integer such that the molecular weight representedby the polyoxypropylene portion of the respective block copolymerconstitutes 20% of the respective block copolymer.
 85. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 84, wherein the average total molecular weight of saidsubstantially pure block copolymer composition is between 1,200 Daltonsand 2,400 Daltons.
 86. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim34, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 6,000 and 13,000 Daltons.87. A substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition of claim 35, wherein the polyoxypropylene portionof the respective block copolymer has a molecular weight range ofbetween 1,200 Daltons and 6,500 Daltons.
 88. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim35, wherein the polyoxyethylene portion of the respective blockcopolymer constitutes between 10% and 95% of the respective blockcopolymer.
 89. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 35, wherein the polyoxyethyleneportion of the respective block copolymer constitutes between 5% and 15%of the respective block copolymer.
 90. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim35, wherein the polyoxyethylene portion of the respective blockcopolymer constitutes 20% of the respective block copolymer.
 91. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 35, wherein a and b are selected such that theaverage total molecular weight of said substantially pure blockcopolymer composition is between 5,000 Daltons and 15,000 Daltons.
 92. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 87, wherein a and b are selected such that theaverage total molecular weight of said substantially pure blockcopolymer composition is between 5,000 Daltons and 15,000 Daltons.
 93. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 88, wherein a and b are selected such that theaverage total molecular weight of said substantially pure blockcopolymer composition is between 5,000 Daltons and 15,000 Daltons.
 94. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 90, wherein a and b are selected such that theaverage total molecular weight of said substantially pure blockcopolymer composition is between 5,000 Daltons and 15,000 Daltons.
 95. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 89, wherein the average total molecular weight ofsaid substantially pure block copolymer composition is between 3,000Daltons and 5,500 Daltons.
 96. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim89, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 4,500 Daltons and 5,500Daltons.
 97. A substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition of claim 35, wherein a is an integer such that themolecular weight of the polyoxypropylene portion of the respective blockcopolymer is 1,750 Daltons and the average total molecular weight ofsaid substantially pure block copolymer composition is between 8,300Daltons and 9,400 Daltons.
 98. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim35, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 1,750Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 8,400 Daltons.
 99. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 87, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 1,750Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 8,400 Daltons.
 100. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 88, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 1,750Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 8,400 Daltons.
 101. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 90, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 1,750Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 8,400 Daltons.
 102. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 35, wherein the average total molecular weight of saidsubstantially pure block copolymer composition is between 5,000 Daltonsand 15,000 Daltons and b is an integer such that the molecular weightrepresented by the polyoxyethylene portion of the respective blockcopolymer constitutes between 75% and 85% of the respective blockcopolymer.
 103. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 102, wherein b is an integer suchthat the molecular weight represented by the polyoxyethylene portion ofthe respective block copolymer constitutes 80% of the respective blockcopolymer.
 104. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 35, wherein the average totalmolecular weight of said substantially pure block copolymer compositionis between 7,000 and 12,000 Daltons.
 105. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim87, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 7,000 and 12,000 Daltons.106. A substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition of claim 88, wherein the average total molecularweight of said substantially pure block copolymer composition is between7,000 and 12,000 Daltons.
 107. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim90, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 7,000 and 12,000 Daltons.108. A substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition of claim 103, wherein the average total molecularweight of said substantially pure block copolymer composition is between7,000 and 12,000 Daltons.
 109. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim35, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 9,700Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 10,000 Daltons.
 110. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 35, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 3,400Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 4,000 Daltons.
 111. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 35, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is between950 Daltons and 4,000 Daltons and b is an integer such that themolecular weight represented by polyoxeythylene portion of therespective block copolymer constitutes between 50% and 95% of therespective block copolymer.
 112. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim35, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 5,000 Daltons and 15,000Daltons and a is an integer such that the molecular weight representedby the polyoxypropylene portion of the respective block copolymerconstitutes between 15% and 25% of the respective block copolymer. 113.A substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 35, wherein the average total molecular weight ofsaid substantially pure block copolymer composition is between 1,200Daltons and 5,300 Daltons and a is an integer such that the molecularweight represented by the polyoxypropylene portion of the respectiveblock copolymer constitutes between 10% and 50% of the respective blockcopolymer.
 114. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 113, wherein the average totalmolecular weight of said substantially pure block copolymer compositionis between 1,750 Daltons and 4,500 Daltons.
 115. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim35, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 1,000 Daltons and 2,600Daltons and a is an integer such that the molecular weight representedby the polyoxypropylene portion of the respective block copolymerconstitutes 20% of the respective block copolymer.
 116. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 115, wherein the average total molecular weight of saidsubstantially pure block copolymer composition is between 1,200 Daltonsand 2,400 Daltons.
 117. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim36, wherein the polyoxypropylene portion of the respective blockcopolymer has a molecular weight range of between 1,200 Daltons and6,500 Daltons.
 118. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim36, wherein the polyoxyethylene portion of the respective blockcopolymer constitutes between 10% and 95% of the respective blockcopolymer.
 119. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 36, wherein the polyoxyethyleneportion of the respective block copolymer constitutes between 5% and 15%of the respective block copolymer.
 120. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim36, wherein the polyoxyethylene portion of the respective blockcopolymer constitutes 20% of the respective block copolymer.
 121. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 36, wherein a and b are selected such that theaverage total molecular weight of said substantially pure blockcopolymer composition is between 5,000 Daltons and 15,000 Daltons. 122.A substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 117, wherein a and b are selected such that theaverage total molecular weight of said substantially pure blockcopolymer composition is between 5,000 Daltons and 15,000 Daltons. 123.A substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 118, wherein a and b are selected such that theaverage total molecular weight of said substantially pure blockcopolymer composition is between 5,000 Daltons and 15,000 Daltons. 124.A substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 120, wherein a and b are selected such that theaverage total molecular weight of said substantially pure blockcopolymer composition is between 5,000 Daltons and 15,000 Daltons. 125.A substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 119, wherein the average total molecular weight ofsaid substantially pure block copolymer composition is between 3,000Daltons and 5,500 Daltons.
 126. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim119, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 4,500 Daltons and 5,500Daltons.
 127. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 36, wherein a is an integer suchthat the molecular weight of the polyoxypropylene portion of therespective block copolymer is 1,750 Daltons and the average totalmolecular weight of said substantially pure block copolymer compositionis between 8,300 Daltons and 9,400 Daltons.
 128. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim36, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 1,750Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 8,400 Daltons.
 129. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 117, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 1,750Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 8,400 Daltons.
 130. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 118, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 1,750Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 8,400 Daltons.
 131. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 120, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 1,750Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 8,400 Daltons.
 132. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 36, wherein the average total molecular weight of saidsubstantially pure block copolymer composition is between 5,000 Daltonsand 15,000 Daltons and b is an integer such that the molecular weightrepresented by the polyoxyethylene portion of the respective blockcopolymer constitutes between 75% and 85% of the respective blockcopolymer.
 133. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 132, wherein b is an integer suchthat the molecular weight represented by the polyoxyethylene portion ofthe respective block copolymer constitutes 80% of the respective blockcopolymer.
 134. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 36, wherein the average totalmolecular weight of said substantially pure block copolymer compositionis between 7,000 and 12,000 Daltons.
 135. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim117, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 7,000 and 12,000 Daltons.136. A substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition of claim 118, wherein the average total molecularweight of said substantially pure block copolymer composition is between7,000 and 12,000 Daltons.
 137. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim120, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 7,000 and 12,000 Daltons.138. A substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition of claim 133, wherein the average total molecularweight of said substantially pure block copolymer composition is between7,000 and 12,000 Daltons.
 139. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim36, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 9,700Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 10,000 Daltons.
 140. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 36, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 3,400Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 4,000 Daltons.
 141. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 36, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is between950 Daltons and 4,000 Daltons and b is an integer such that themolecular weight represented by polyoxeythylene portion of therespective block copolymer constitutes between 50% and 95% of therespective block copolymer.
 142. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim36, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 5,000 Daltons and 15,000Daltons and a is an integer such that the molecular weight representedby the polyoxypropylene portion of the respective block copolymerconstitutes between 15% and 25% of the respective block copolymer. 143.A substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 36, wherein the average total molecular weight ofsaid substantially pure block copolymer composition is between 1,200Daltons and 5,300 Daltons and a is an integer such that the molecularweight represented by the polyoxypropylene portion of the respectiveblock copolymer constitutes between 10% and 50% of the respective blockcopolymer.
 144. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 143, wherein the average totalmolecular weight of said substantially pure block copolymer compositionis between 1,750 Daltons and 4,500 Daltons.
 145. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim36, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 1,000 Daltons and 2,600Daltons and a is an integer such that the molecular weight representedby the polyoxypropylene portion of the respective block copolymerconstitutes 20% of the respective block copolymer.
 146. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 145, wherein the average total molecular weight of saidsubstantially pure block copolymer composition is between 1,200 Daltonsand 2,400 Daltons.
 147. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim37, wherein the polyoxypropylene portion of the respective blockcopolymer has a molecular weight range of between 1,200 Daltons and6,500 Daltons.
 148. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim37, wherein the polyoxyethylene portion of the respective blockcopolymer constitutes between 10% and 95% of the respective blockcopolymer.
 149. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 37, wherein the polyoxyethyleneportion of the respective block copolymer constitutes between 5% and 15%of the respective block copolymer.
 150. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim37, wherein the polyoxyethylene portion of the respective blockcopolymer constitutes 20% of the respective block copolymer.
 151. Asubstantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 37, wherein a and b are selected such that theaverage total molecular weight of said substantially pure blockcopolymer composition is between 5,000 Daltons and 15,000 Daltons. 152.A substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 147, wherein a and b are selected such that theaverage total molecular weight of said substantially pure blockcopolymer composition is between 5,000 Daltons and 15,000 Daltons. 153.A substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 148, wherein a and b are selected such that theaverage total molecular weight of said substantially pure blockcopolymer composition is between 5,000 Daltons and 15,000 Daltons. 154.A substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 150, wherein a and b are selected such that theaverage total molecular weight of said substantially pure blockcopolymer composition is between 5,000 Daltons and 15,000 Daltons. 155.A substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 149, wherein the average total molecular weight ofsaid substantially pure block copolymer composition is between 3,000Daltons and 5,500 Daltons.
 156. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim149, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 4,500 Daltons and 5,500Daltons.
 157. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 37, wherein a is an integer suchthat the molecular weight of the polyoxypropylene portion of therespective block copolymer is 1,750 Daltons and the average totalmolecular weight of said substantially pure block copolymer compositionis between 8,300 Daltons and 9,400 Daltons.
 158. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim37, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 1,750Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 8,400 Daltons.
 159. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 147, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 1,750Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 8,400 Daltons.
 160. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 148, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 1,750Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 8,400 Daltons.
 161. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 150, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 1,750Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 8,400 Daltons.
 162. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 37, wherein the average total molecular weight of saidsubstantially pure block copolymer composition is between 5,000 Daltonsand 15,000 Daltons and b is an integer such that the molecular weightrepresented by the polyoxyethylene portion of the respective blockcopolymer constitutes between 75% and 85% of the respective blockcopolymer.
 163. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 162, wherein b is an integer suchthat the molecular weight represented by the polyoxyethylene portion ofthe respective block copolymer constitutes 80% of the respective blockcopolymer.
 164. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 37, wherein the average totalmolecular weight of said substantially pure block copolymer compositionis between 7,000 and 12,000 Daltons.
 165. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim147, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 7,000 and 12,000 Daltons.166. A substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition of claim 148, wherein the average total molecularweight of said substantially pure block copolymer composition is between7,000 and 12,000 Daltons.
 167. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim150, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 7,000 and 12,000 Daltons.168. A substantially pure polyoxypropylene/polyoxyethylene blockcopolymer composition of claim 163, wherein the average total molecularweight of said substantially pure block copolymer composition is between7,000 and 12,000 Daltons.
 169. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim37, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 9,700Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 10,000 Daltons.
 170. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 37, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is 3,400Daltons and the average total molecular weight of said substantiallypure block copolymer composition is 4,000 Daltons.
 171. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 37, wherein a is an integer such that the molecular weight of thepolyoxypropylene portion of the respective block copolymer is between950 Daltons and 4,000 Daltons and b is an integer such that themolecular weight represented by polyoxeythylene portion of therespective block copolymer constitutes between 50% and 95% of therespective block copolymer.
 172. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim37, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 5,000 Daltons and 15,000Daltons and a is an integer such that the molecular weight representedby the polyoxypropylene portion of the respective block copolymerconstitutes between 15% and 25% of the respective block copolymer. 173.A substantially pure polyoxypropylene/polyoxyethylene block copolymercomposition of claim 37, wherein the average total molecular weight ofsaid substantially pure block copolymer composition is between 1,200Daltons and 5,300 Daltons and a is an integer such that the molecularweight represented by the polyoxypropylene portion of the respectiveblock copolymer constitutes between 10% and 50% of the respective blockcopolymer.
 174. A substantially pure polyoxypropylene/polyoxyethyleneblock copolymer composition of claim 173, wherein the average totalmolecular weight of said substantially pure block copolymer compositionis between 1,750 Daltons and 4,500 Daltons.
 175. A substantially purepolyoxypropylene/polyoxyethylene block copolymer composition of claim37, wherein the average total molecular weight of said substantiallypure block copolymer composition is between 1,000 Daltons and 2,600Daltons and a is an integer such that the molecular weight representedby the polyoxypropylene portion of the respective block copolymerconstitutes 20% of the respective block copolymer.
 176. A substantiallypure polyoxypropylene/polyoxyethylene block copolymer composition ofclaim 175, wherein the average total molecular weight of saidsubstantially pure block copolymer composition is between 1,200 Daltonsand 2,400 Daltons.